UNIVERSITATIS OULUENSIS MEDICA ACTA D D 1538 ACTA Susanna Ylönen OULU 2019 D 1538 Susanna Ylönen GENETIC RISK FACTORS FOR MOVEMENT DISORDERS IN FINLAND UNIVERSITY OF OULU GRADUATE SCHOOL; UNIVERSITY OF OULU, FACULTY OF MEDICINE; MEDICAL RESEARCH CENTER OULU; OULU UNIVERSITY HOSPITAL
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UNIVERSITY OF OULU P .O. Box 8000 F I -90014 UNIVERSITY OF OULU FINLAND
A C T A U N I V E R S I T A T I S O U L U E N S I S
University Lecturer Tuomo Glumoff
University Lecturer Santeri Palviainen
Senior research fellow Jari Juuti
Professor Olli Vuolteenaho
University Lecturer Veli-Matti Ulvinen
Planning Director Pertti Tikkanen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-2397-1 (Paperback)ISBN 978-952-62-2398-8 (PDF)ISSN 0355-3221 (Print)ISSN 1796-2234 (Online)
U N I V E R S I TAT I S O U L U E N S I S
MEDICA
ACTAD
D 1538
AC
TASusanna Ylönen
OULU 2019
D 1538
Susanna Ylönen
GENETIC RISK FACTORSFOR MOVEMENT DISORDERS IN FINLAND
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;MEDICAL RESEARCH CENTER OULU;OULU UNIVERSITY HOSPITAL
ACTA UNIVERS ITAT I S OULUENS I SD M e d i c a 1 5 3 8
SUSANNA YLÖNEN
GENETIC RISK FACTORS FOR MOVEMENT DISORDERS IN FINLAND
Academic dissertation to be presented with the assentof the Doctoral Training Committee of Health andBiosciences of the University of Oulu for public defencein Auditorium 8 of Oulu University Hospital (Kajaanintie50), on 15 November 2019, at 12 noon
Reviewed byAssociate Professor Andrea Carmine BelinProfessor Arto Mannermaa
ISBN 978-952-62-2397-1 (Paperback)ISBN 978-952-62-2398-8 (PDF)
ISSN 0355-3221 (Printed)ISSN 1796-2234 (Online)
Cover DesignRaimo Ahonen
JUVENES PRINTTAMPERE 2019
OpponentDocent Annakaisa Haapasalo
Ylönen, Susanna, Genetic risk factors for movement disorders in Finland. University of Oulu Graduate School; University of Oulu, Faculty of Medicine; MedicalResearch Center Oulu; Oulu University HospitalActa Univ. Oul. D 1538, 2019University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
Parkinson’s disease and Huntington’s disease are progressive neurodegenerative movementdisorders that typically manifest in adulthood. In this study, genetic risk factors contributing tothese two movement disorders were investigated in Finnish patients. Patients with early-onset orlate-onset Parkinson’s disease as well as population controls were examined. The p.L444Pmutation in GBA was found to contribute to the risk of Parkinson’s disease. POLG1 compoundheterozygous mutations were detected in two patients with Parkinson’s disease and rare lengthvariants in POLG1 were associated with Parkinson’s disease. Variants in SMPD1, LRRK2 orCHCHD10, previously detected in other populations, were not detected, suggesting that they arerare or even absent in the Finnish population. Patients with Huntington’s disease were investigatedfor HTT gene haplotypes as well as whether these haplotypes alter the stability of the elongatedCAG repeat. Haplogroup A was less common in Finns than in other European populations,whereas it was significantly more common in patients with Huntington’s disease than in thegeneral population. Certain HTT haplotypes as well as the parental gender were found to affect therepeat instability. We found that compound heterozygous mutations in POLG1 were causative ofParkinson’s disease, rare length variants in POLG1 were associated with Parkinson’s disease andGBA p.L444P was significantly more frequent in patients than in the controls, which suggests thatthese mutations are associated with the development of Parkinson’s disease. The low prevalenceof Huntington’s disease in Finland correlates with the low frequency of the disease-associatedHTT haplogroup A. Paternal inheritance combined with haplotype A1 increased the risk of repeatexpansion. Movement disorders in Finland were found to share some of the same genetic riskfactors found in other European populations, but some other recognized genetic variants could notbe detected.
Ylönen, Susanna, Liikehäiriösairauksien geneettisiä riskitekijöitä Suomessa. Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Medical ResearchCenter Oulu; Oulun yliopistollinen sairaalaActa Univ. Oul. D 1538, 2019Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Parkinsonin tauti ja Huntingtonin tauti ovat hermostoa rappeuttavia eteneviä liikehäiriösairauk-sia, jotka tyypillisesti ilmenevät aikuisiällä. Tässä tutkimuksessa selvitettiin näiden kahden liike-häiriösairauden geneettisiä riskitekijöitä suomalaisilla potilailla. Tutkimme potilaita, joilla olivarhain alkava Parkinsonin tauti tai myöhään alkava Parkinsonin tauti sekä väestökontrolleja.GBA-geenin p.L444P mutaation havaittiin lisäävän Parkinsonin taudin riskiä. Kaksi Parkinsonintautia sairastavaa potilasta oli yhdistelmäheterotsygootteja haitallisten POLG1-geenin variant-tien suhteen ja harvinaiset POLG1 CAG toistojaksovariantit assosioituivat Parkinsonin tautiin.Tutkittuja variantteja SMPD1-, LRRK2- ja CHCHD10-geeneissä ei löydetty tästä aineistostalainkaan, mikä viittaa siihen, että ne puuttuvat suomalaisesta väestöstä tai ovat harvinaisia. Hun-tingtonin tautia sairastavilta potilailta tutkittiin HTT-geenin haploryhmiä ja niiden vaikutustaHuntingtonin tautia aiheuttavan pidentyneen toistojakson epästabiiliuteen. Haploryhmä A olisuomalaisessa väestössä harvinainen verrattuna eurooppalaiseen väestöön ja se oli huomattavas-ti yleisempi Huntingtonin tautipotilailla kuin väestössä. Toistojakson epästabiiliuteen vaikutti-vat tietyt HTT-geenin haplotyypit samoin kuin sen vanhemman sukupuoli, jolta pidentynyt tois-tojakso periytyy. POLG1 yhdistelmäheterotsygoottien katsottiin aiheuttavat Parkinsonin tautia jaharvinaisten POLG1 CAG toistojaksovarianttien todettiin assosioituvan Parkinsonin tautiin Suo-messa. GBA p.L444P mutaatio merkittävästi yleisempi Parkinsonin tautipotilailla kuin kontrol-leilla, mikä viittaa siihen, että se on Parkinsonin taudin riskitekijä. Huntingtonin tautiin assosioi-tuvan haploryhmä A:n matala frekvenssi selittää taudin vähäistä esiintyvyyttä Suomessa. Pater-naalinen periytyminen ja haplotyyppi A1 lisäsivät HTT-geenin toistojakson pidentymisen riskiä.Liikehäiriösairauksilla todettiin Suomessa osittain samanlaisia riskitekijöitä kuin muualla Euroo-passa, mutta kaikkia tutkittuja variantteja emme havainneet.
SANDO sensory ataxic neuropathy dysarthria and ophthalmoparesis
SAP sphingolipid activator protein
SMAJ late-onset spinal motor neuropathy
SMPD1 Sphingomyelin phosphodiesterase 1 (gene)
SNCA α-synuclein (gene)
SNP single nucleotide polymorphism
TFAM mitochondrial transcription factor A (gene)
WD40 Trp-Asp-40
WES whole exome sequencing
wt wild type
13
Original publications
This thesis is based on the following publications, which are referred throughout
the text by their Roman numerals:
I Ylönen, S., Ylikotila, P., Siitonen, A., Finnilä, S., Autere, J., & Majamaa, K. (2013). Variations of mitochondrial DNA polymerase γ in patients with Parkinson's disease. Journal of Neurology, 260(12), 3144-3149.
II Ylönen, S., Siitonen, A., Nalls, M.A., Ylikotila, P., Autere, J., Eerola-Rautio, J., Gibbs, R., Hiltunen, M., Tienari, P.J., Soininen, H., Singleton, A.B., & Majamaa, K. (2017). Genetic risk factors in Finnish patients with Parkinson's disease. Parkinsonism and Related Disorders, 45, 39-43.
III Ylönen, S., Sipilä, J., Hietala, M. & Majamaa K. (2019) HTT haplogroups in Finnish patients with Huntington disease. Neurology Genetics, 5(3), e334.
using 563 STAMPEED population controls from the North Finland Birth Cohort
1966 as controls. (Siitonen et al., 2017) The 10 x depth of the contigs was at least
90 % and the 30 x depth of the contigs was approximately 70 % on average. The
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variants were filtered by using a 99.9% tranche and the variants that passed the
filter were then selected for subsequent analysis. No further filtering was made in
order to improve sensitivity. Functional annotations were made by Annovar,
SNPEff and SNPSift using default settings. Sequencing was used to verify
nonsynonymous variants in LRRK2 and SMPD1 that were more frequent in patients
than in controls.
4.5 Bioinformatics
Data of Finnish controls from the Exome Aggregation Consortium (ExAC) were
compared with the data we obtained from WES. The variants discovered by WES
were analysed with PredictSNP in order to estimate their pathogenicity. PredictSNP
is a consensus prediction tool that uses multiple prediction tools to estimate the
effect of amino acid changes. The PredictSNP score has values between −1 and +1.
The mutations are considered to be neutral, if the score is < 0, and deleterious, if
the score is ≥ 0. The absolute distance of the PredictSNP score from zero expresses
the confidence of the consensus classifier about its prediction. (Bendl et al., 2014)
4.6 Statistics
Fisher’s exact test was used to compare allele frequencies in patients and controls.
Exact test of population differentiation was used to analyse the distribution of CAG
length variants in POLG1.
4.7 Ethics
All samples were coded to prevent direct identification of individual patients. The
use of DNA samples from the controls was approved by the Ethics committee of
the Finnish Red Cross. The PD study was approved by the Ethics Committee of
Hospital District of Southwest Finland, the Ethics Committee of the Medical
Faculty of the University of Kuopio and the Ethics Committee of Helsinki
University Hospital. Written informed consent was obtained from the patients
participating in the study. The HD study has been approved by the Ethics
Committee of Hospital District of Southwest Finland (Dnro ETMK 19/180/2010)
and received the national study permits from the National Institute for Health and
Welfare (Dnro THL/1456/5.05.00/2010) and the National Supervisory Authority
43
for Welfare and Health, Valvira (Dnro 1195/06.01.03.01/2012). The study involved
no contact with patients and therefore, no informed consent was required.
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5 Results
5.1 POLG1 and Parkinson’s disease (I, II)
Nine POLG1 mutations were screened in 441 patients with EOPD and in 263
patients belonging to a case series collected in the Kuopio University Hospital
(Table 3). Heterozygous mutations were detected in 32 patients (EOPD, N=20;
LOPD, N=12). The most common mutations were p.W748S in 12 patients,
p.G517V in nine patients and p.R722H in eight patients. The p.E1143G allele was
screened in patients with p.W748S and it was present in all these patients. The allele
frequencies among the patients were not significantly different from those in the
controls. One patient was compound heterozygous for the p.[(T251I; P587L)] allele
and the p.[(W748S; E1143G)] allele, which was confirmed with a segregation
analysis. Sequencing of the coding region in the 32 patients revealed three more
patients with more than one POLG1 mutant allele. One of these could be confirmed
as a compound heterozygote, but for the two others, a segregation analysis could
not be performed, and it remains unknown if the mutations were in trans. Clinically,
there was no difference between patients with or without POLG1 mutations.
However, the EOPD patients with POLG1 mutations had more often affected
siblings than those without these mutations.
POLG1 CAG repeat was analyzed in 496 patients with EOPD and 209 patients
with LOPD. The CAG repeat length was found to vary between eight and 13 repeats
in our samples with ten repeats being the most common repeat length. The non-
10Q alleles were significantly more common in EOPD patients than in controls (p=
0.0056 for difference). The non-10Q/non-10Q genotypes were found in seven
EOPD patients but in none of the controls.
5.2 Genetic risk factors for Parkinson’s disease (II)
Patients with EOPD were then screened for variants that have been reported to
increase the risk of PD. None of the variants (p.L302P in SMPD1, p.R1441C/G/H
or p.G2019S in LRRK2, p.S59L or p.G66V in CHCHD10) were detected. The
frequency of the MAPT haplotype H1 was 92.6% in EOPD patients and 95.0% in
292 controls (p = 0.068 for difference). The p.N370S variant in GBA was found in
0.4% of EOPD patients and 0.3% of controls and p.L444P was found in 2.0% of
EOPD patients and 0.5% of controls (p = 0.032, Fisher's exact test). Three of the
46
patients with p.L444P had an additional nonsynonymous p.A456P variant and the
synonymous rs1135675 variant at codon 460. These variants form together the
RecNciI allele. One patient harboring the p.N370S also had the POLG1 variants
p.N468D and p.A1105T mentioned earlier.
In a similar fashion, the variants in SMPD1, LRRK2 or CHCHD10 were not
found in 323 LOPD patients and the frequency of MAPT haplotype H1 was 94.4%
(p = 0.73 for difference). The p.N370S variant in GBA was found in 0.6% of LOPD
patients and p.L444P in 1.2%.
WES revealed five nonsynonymous variants that were not present in Finnish
ExAC controls. These variants were p.C1152F, p.S1627L and p.R1628P in LRRK2
and p.E358K and p.R542Q in SMPD1. Two of the variants, p.R1628P in LRRK2
and p.R542Q in SMPD1 were predicted by PredictSNP to be deleterious, while the
remaining variants were predicted to be neutral.
Table 6. PD patients with detected missense variants.
gene variant EOPD n (%) LOPD n (%) Controls %
GBA p.N370S 2 (0.4) 2 (0.6) 0.3
p.L444P 13 (2.5) 4 (1.2) 0.5
POLG1 p.T251I 2 (0.5) 0 (<0.4) 0.7
p.N468D 1 (0.2) 1 (0.4) <0.1
p.G517V 6 (1.4) 3 (1.1) 0.2
p.P587L 2 (0.5) 0 (<0.4) 0.7
p.R722H 5 (1.1) 3 (1.1) 0.7
p.W748S 8 (1.8) 4 (1.5) 0.8
p.A1105T 1 (0.2) 0 (<0.4) <0.1
SMPD1 p.E358K 1 (0.4) n.a. <0.02
p.R542Q 1 (0.4) n.a. <0.02
LRRK2 p.C1152F 1 (0.4) n.a. <0.2
p.S1627L 1 (0.4) n.a. <0.2
p.R1628P 2 (0.9) n.a. <0.02
EOPD, patients with early onset Parkinson’s disease; LOPD, patients with late onset Parkinson’s disease;
n.a., not analyzed.
5.3 HTT haplotypes (III)
The allele frequencies of the HTT haplotypes were significantly different in patients
and controls (p < 0.00001, exact test of population differentiation). The haplogroup
A was more common in patients, while haplogroups B and C were more common
in controls (See III table 1 for details). There were also significant differences in
47
the distribution of the haplotypes A1-A5 between patients and controls (p <
0.00001, exact test of population differentiation). Haplotypes A1 and A2 were more
common in patients whereas haplotypes A4 and A5 more often present in controls
(p = 0.003, exact test of population differentiation). Haplogroup A was less
common in our population samples as compared to other European populations
(Warby et al., 2011) (p = 0.0003, X2 test). The proportion of haplotypes A1 and A2
within the haplogroup A was similar to that in European populations.
The change in the CAG repeat length could be determined in 65 transmissions,
41 maternal and 24 paternal. In 50 of these transmissions, the CAG repeat could be
phased with the haplotype. There were 38 transmissions with haplogroup A, 10
with haplogroup C and two with other haplogroups. The mean change in CAG
repeat length was associated with haplotypes (table 7).
Table 7. The mean change (N) in CAG repeat lengths in intergenerational transmissions.
haplotype paternal maternal
A1 9.4 -1.5
A2 1.3 1
A3 6.2 0.5
A 7 0.3
C -3.1 -1.8
total 1.4 -0.2
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49
6 Discussion
We investigated genetic risk factors in Finnish patients with well-known movement
disorders, i.e. Parkinson’s disease or Huntington’s disease. Two patients with
confirmed compound heterozygous mutations in POLG1 were detected among the
EOPD patients. We also found co-occurring POLG1 variants in two additional
patients, but we could not confirm if these variants were compound heterozygotes
or if they were located in the same allele. A significant difference in the POLG1
CAG repeat distribution could be detected between EOPD and controls, GBA
p.L444P was significantly more frequent in PD patients than in controls.
Interestingly, we did not detect the p.G2019S variant in LRRK2, although it has
been found in many European populations. We observed highly significant
differences in haplotype distribution between HD patients and controls.
Haplogroup A was less common in the Finnish population than in Caucasian
populations in general. Intergenerational CAG repeat instability was associated
with haplotypes and parental gender.
6.1 Mitochondria in Parkinson’s disease (I, II)
Two lines of evidence supporting the role of mitochondria in PD emerged from this
study. (1) We identified EOPD patients with compound heterozygous mutations in
POLG1, and (2) affected siblings were more frequent in EOPD patients with
heterozygous POLG1 mutations than in patients without these mutations.
Compound heterozygous mutations have been reported in patients with
parkinsonism previously (Davidzon et al., 2006; Luoma et al., 2004; Rempe et al.,
2016). Pathogenic mutations in POLG1 make the polymerase error prone, which
subsequently leads to mutations in mtDNA. This results in variable phenotypes
through mitochondrial failure. POLG1-related parkinsonism is often accompanied
with other symptoms or syndromes such as PEO or SANDO. It is responsive to
levodopa.
We searched PubMed for POLG or POLG1 and Parkinson or parkinsonism and
the subsequent review revealed 24 articles that had described POLG1 mutations in
patients with parkinsonism or PD. Fifteen of these articles were case reports, four
were small case series and five were epidemiological studies. In these articles, 41
different POLG1 variants were described in association with parkinsonism,
whereas in patients with idiopathic Parkinson’s disease, 17 different POLG1
variants were found at similar frequencies as in controls. Patients with
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parkinsonism were usually also showing signs of PEO and occasionally there were
additional symptoms such as neuropathy and premature menopause. Each variant
had been described in one to five articles. The variants were distributed in all three
domains. The variants were usually found in either a heterozygous or compound
heterozygous state and only four studies reported homozygous variants. One of
them described a homozygous p.W748S mutation in a patient with ataxia,
parkinsonism, ophthalmoplegia, peripheral neuropathy, and sensorineural hearing
loss (Remes et al., 2008). The most commonly described POLG1 variants were
p.Y831C and p.Y955C, p.A467T, p.W748S. This list of variants is slightly different
from our list of screened variants, which were considered to be common variants
at the time of the study. However, p.Y831C has been found in controls at similar
frequencies as in patients and it is currently considered as a neutral polymorphism
(Gui et al., 2012; Hudson et al., 2009; Luoma et al., 2007; Tiangyou et al., 2006).
All of the described variants are not necessarily pathogenic. Twenty-two of the 41
variants have been described in association with PEO in Human DNA Polymerase
Gamma Mutation Database. Some of the variants have been reported together with
other variants. In the compound heterozygous state, different variants could act
together to form the pathogenic state or one of the variants could partly compensate
for the malfunction cause by some other variant. This review of the literature
suggests that there are no typical POLG1 variants causing parkinsonism, instead
there are several different variants scattered along the gene.
We found two patients with compound heterozygous mutations in the POLG1
gene among 450 patients with EOPD, suggesting it has a frequency of 4.4/1000.
One patient harbored p.T251I and p.P587L in one allele and p.W748S and
p.E1143G in the other allele, and the other patient harbored p.N468D and A1105T
in the two alleles. Two further patients with more than one heterozygous variant
were detected, but we could not determine if these were in cis or in trans. We
considered the compound heterozygotes to be causal for PD. The frequencies of
single heterozygous variants did not differ significantly from the controls
suggesting that they are not a risk factor of PD. Previous cohort studies on PD (Gui
et al., 2012; Hudson et al., 2009; Luoma et al., 2007; Tiangyou et al., 2006) or
atypical parkinsonism (Synofzik et al., 2012) have reported some cases in which
POLG1 variants seemed to be responsible for PD, but generally POLG1 variants
have been found at similar frequencies in PD patients as in controls. In case reports
and small case series, the phenotype was parkinsonism usually with PEO.
The three most common heterozygous variants among PD patients were
p.G517V (1.3%), p.R722H (1.1%) and p.W748S (1.7%). The frequencies of these
51
variants did not differ significantly from population frequencies. The p.G517V
variant has been reported to associate with mitochondrial disorders, but a
biochemical analysis has revealed that p.G517V decreases only slightly polymerase
activity and the affinity of p55 accessory subunit (Kasiviswanathan & Copeland,
2011). However, possible effects on fidelity were not investigated. p.R722H is
considered to be pathogenic, as it has been found to be homozygous in two Finnish
families with a mitochondrial disease phenotype. It is located in an evolutionarily
conserved domain in the linker region, although p.R722 itself is not extensively
conserved. The homologous region in E. coli is thought to be involved in DNA-
binding. Therefore, it has been speculated that the loss of arginine might affect the
DNA-binding properties and hence the fidelity of binding. The carrier frequency is
estimated to be 1:135 in the Finnish population. (Komulainen et al., 2010)
p.W748S and p.A467T are definitely pathogenic. They both are located in the
linker region of POLG1, and they have been identified previously in patients with
PD or parkinsonism (Gui et al., 2012; Hudson et al., 2009; Remes et al., 2008;
Synofzik et al., 2012; Tiangyou et al., 2006). The p.W748S variant was found with
p.E1143G in patients. This allele has a carrier frequency of 1:125 in the Finnish
population, and it is associated with mitochondrial recessive ataxia syndrome
(MIRAS) (Hakonen et al., 2005) as well as some other neurological phenotypes
when present in the homozygous state (Palin et al., 2010). It seems to be rare in PD
but has been found in parkinsonism (Remes et al., 2008). It is an ancient allele of
European origin possibly originating from Scandinavia, and it has been distributed
extensively during Viking times, later even spreading to Australia and New Zealand
via immigration from Europe (Hakonen et al., 2007). In Norway, its estimated
carrier frequency is 1:100 (Winterthun et al., 2005). p.A467T also seems to be of
ancient European origin. (Hakonen et al., 2007) It has been found to severely impair
the polymerase function (Luoma et al., 2005). The carrier frequency has been
estimated to be <1:500 in the Finnish population (Luoma et al., 2005), and 1:100
in Norway (Winterthun et al., 2005).
Several neurodegenerative diseases result from expanded trinucleotide repeats.
In the CAG repeat of POLG1, large expansions have not been detected, but instead
variations between 5 and 16 trinucleotides, with 10Q being the most frequent allele
(Anvret et al., 2010; Balafkan et al., 2012). We found an association between non-
10Q alleles and PD. Some previous studies have found an association either with
the non-10/11Q (Anvret et al., 2010; Balafkan et al., 2012; Gui et al., 2012; Luoma
et al., 2007) or non-10Q (Eerola et al., 2010), while others have not detected any
significant associations (Hudson et al., 2009; Tiangyou et al., 2006) In silico
52
analysis predicted that the length variation influences the folding energy of the
protein (Anvret et al., 2010). The non-10Q allele may predispose to PD or it could
act as a marker for a nearby predisposing allele. No studies investigating the
biochemical consequences of the CAG length variation in vivo could be found. The
deletion of the entire CAG repeat has no effect on the enzymatic properties of
POLG1, but induces a slight up-regulation of its expression (Spelbrink et al., 2000).
One study reported association with increased risk of PD when 9Q was with present
a distinct POLG1 haplotype rather than 9Q or the haplotype alone (Luoma et al.,
2007). In our patients, p.G517V was always accompanied with the POLG1 length
variant 11Q, and 8Q with p.G268A. It is not known, however, if these variants
belonged to the same allele or not.
Mitochondrial dysfunction is considered as one of the mechanisms leading to
PD. Neurons require a constant supply of energy and thus are sensitive to
mitochondrial failure. Some Complex I inhibiting chemicals, including MPTP,
have been observed to evoke parkinsonian symptoms (Langston et al., 1983),
respiratory chain defects have been detected in platelets, muscle and brain of PD
patients. Genes considered to cause PD, including Parkin, PINK1 and DJ-1, have
been shown to regulate mitochondrial functions. Parkin and PINK1 function in a
pathway that removes defective mitochondria from cells (Narendra et al., 2010).
DJ-1 protects cells from oxidative stress (Taira et al., 2004), acts as a transcriptional
activator of the PINK1 gene (Requejo-Aguilar et al., 2015), and interacts with
Parkin (Moore et al., 2005; Tang et al., 2006). Mouse models with a Tfam knockout
developed cytoplasmic inclusions and dopaminergic cell loss, and their symptoms
could be alleviated by levodopa treatment (Ekstrand et al., 2007). POLG1 variants
seem to make only a modest contribution to PD. The mitochondrial pathogenesis
of PD appears to consist of several factors, each adding its own small contribution
to the development of the disease. No single mitochondrial factor that would
explain a substantial portion of PD cases has so far been discovered.
6.2 Genetic risk factors for Parkinson’s disease (II)
Parkinson’s disease is a multifactorial disorder, where both genes and environment
influence the development of the disease. Environmental risk factors include rural
living, drinking well water and pesticide use. The p.G2019S variant in LRRK2 is
common in PD patients in northern African Arab and Ashkenazi Jewish populations
and in the Mediterranean countries. There is a gradient from southern to northern
Europe, where p.G2019S becomes rarer towards the north. In Swedish PD patients
53
with a mean age of 68 years and a mean age of onset of 60 years, the frequency
p.G2019S has been estimated to be 1.4% (Belin et al., 2006). In our study, however,
the p.G2019S was not detected, which indicates that its frequency in Finland is less
than 0.1%.
Putative pathogenic or risk variants in genes causing lysosomal storage
disorders have been found to be overrepresented in PD (Robak et al., 2017). GBA
is the best-known example of these genes. The two most common mutations in
GBA are p.N370S and p.L444P that are found at a frequency of 4%; these account
for 70% of GBA mutation alleles in European PD patients (Lesage et al., 2011). In
Ashkenazi Jewish PD patients, the frequency of the two mutations has been
reported to be as high as 15.3%, with the p.N370S mutation being more common.
In non-Ashkenazi Jewish patients, the frequency was 3.2% (Sidransky et al., 2009).
In a group of predominantly French PD patients, the frequencies were 2.9% for
p.N370S and 1.0% for p.L444P (Lesage et al., 2011). In Russian PD patients, the
frequencies have been estimated at 0.5% for p.N370S and 1.1% for p.L444P
(Emelyanov et al., 2018). In East Asian populations, the p.L444P is common, but
p.N370S seems to be either absent or at least rare (Pulkes et al., 2014). We found
that the frequency of the p.L444P mutation was 2.8% among Finnish PD patients,
being significantly different between patients and controls. In Sweden, the mutation
is clustered in the northern part of the country, where 4.1% of PD patients carry the
mutation, while in the southern Sweden, the mutation is found in 1% of PD patients.
The frequency of Gaucher’s disease is also elevated in northern Sweden (Ran et al.,
2016). The origin of the mutation cluster has been tracked back to the 16th century
to the county of Västerbotten, from where it has spread to Norrbotten (Dahl,
Hillborg, & Olofsson, 1993). PD patients with GBA mutations seem to have an
earlier onset of the disease in comparison to patients without GBA mutations
(Sidransky et al., 2009). The mean age of onset was 44.6 years in the Finnish EOPD
patients with GBA mutations, whereas the mean age of onset was 46.8 years in the
entire cohort.
The SMPD1 p.L302P is one of the mutations that causes Niemann-Pick type A
disease when present in a homozygous state. A heterozygous mutation has been
associated with PD. In an Ashkenazi Jewish population, the mutation was found in
0.1 % of the general population and in 1.0 % of PD patients (Gan-Or et al., 2013)
This mutation has not been found in Chinese or Taiwanese Populations (K. Li et
al., 2015; Mao et al., 2017; Wu, Lin, & Lin, 2014). We did not find the SMPD1
p.L302P among our samples, indicating that it is not a common risk factor for PD
54
in Finland (Kaasinen, Hietala, & Kuoppamäki, 2015). However, two other variants
that were not found in controls were detected by WES.
MAPT haplotype H1 was more common in Finnish population than in other
European populations. Unlike previous studies where the frequency of haplotype
H1 was 81.8% in PD patients and 77.4% in controls (Zabetian et al., 2007), we
could not detect an association between the MAPT haplotype and PD. We detected
haplotype H1 frequencies of 92.6% in EOPD patients and 95.0% in controls. MAPT
haplotype H1 has been associated with progressive supranuclear palsy (PSP) and
corticobasal degeneration (CBD), which are Parkinson-plus syndromes and present
with evidence of tau inclusions (Webb et al., 2008). It is possible that only part of
the variants of haplotype H1 are associated with PD, or alternatively that the genetic
background affects the association pattern. The methylenetetrahydrofolate
reductase gene (MTHFR) encodes for an enzyme involved in regulating
homocysteine levels. The variant C677T may cause elevated plasma homocysteine
levels, and it has been associated with an increased risk of PD in European, but not
in Asian, populations (Zhu, Zhu, He, Liu, & Liu, 2015). However, the analysis of
MTHFR was not included in this study.
The OMIM database lists 23 genes or loci that are associated with PD. Some
of these genes lead to the disease in a Mendelian fashion, while others are risk
factors. The currently known genetic factors, however, do not explain the total
estimated heritability of PD. The estimated heritability of PD is 27%, while GWAS
explains only about 5% (Keller et al., 2012). Rare variants could explain part of the
missing heritability. There is evidence that known PD genes could harbor rare
variants that contribute to PD pathogenicity in addition to the known pathogenic
and risk variants (Jansen et al., 2017). Indeed, we found three variants in LRRK2
and two variants in SMPD1 that were not found in controls. Two of these, one in
LRRK2 and another in SMPD1, were predicted to be deleterious by predictSNP.
Further studies, including functional studies, will be needed in order to evaluate
whether these variants are possible risk factors for PD or if the variants are specific
in the Finnish population. The Finnish PD population appears to differ from other
European populations in that some genetic variants that cause PD in Europe are
absent or rare in Finland. The SNCA mutation p.A53E has been found in three
Finnish families and it likely shares a common founder (Pasanen et al., 2017).
Parkin c.101_102delAG was described in two unrelated Finnish patients (Kaasinen
et al., 2015). This variant has been previously detected in European PD patients.
GBA mutations in Finnish population have similar frequencies as in non-Ashkenazi
55
Jewish populations in Europe. So far, no typically Finnish genetic variant has
emerged that would explain a substantial proportion of PD cases in Finland.
6.3 Huntington’s disease (III)
The prevalence of HD varies greatly in different populations, being high in most
European populations and low in East Asian populations. In Venezuela, around
Lake Maracaibo, there is a population with an exceptionally high prevalence of HD,
being 700/100 000; in contrast, in Iceland, the prevalence is very low, only 0.96/100
000 (Sveinsson, Halldórsson, & Olafsson, 2012). The prevalence in Finland is
lower than in most European populations. Finnish and Icelandic populations are
isolated and founder effects are thought to explain the lower prevalence.
We found that the frequency of haplogroup A was significantly higher in
Finnish HD patients than that in population controls and haplogroup C was more
common in controls. In particular, haplotypes A1 and A2 were common among HD
patients. The pattern resembles that seen in other European populations, where
haplotypes A1-3 have been associated with HD, whereas haplotypes A4 and A5 are
considered to be protective. The frequencies of haplotypes A1 and A2 have been
found to correlate with the prevalence of HD (Warby et al., 2009). In European
populations, HD occurs predominantly with haplogroup A. In East Asian
populations, haplogroup A is rare and HD-associated haplotypes A1 and A2 are
absent. Instead, most HD cases are associated with haplogroup C. In the Finnish
population, haplogroup A is less common than in other European populations and
this partly explains the lower prevalence of HD.
Paternal transmission has been shown to drive intergenerational HTT CAG
expansions, while maternal transmissions are more likely to be stable or lead to
contractions (Aziz, van Belzen, Coops, Belfroid, & Roos, 2011). Indeed, we
observed a tendency for expansions in paternal transmissions and for contractions
in maternal transmissions. The haplotype was also found to affect the changes in
the CAG length. In haplotype A1, the size of the CAG repeat tended to increase in
paternal transmissions and decrease in maternal transmission. Haplotypes A2 and
A3 were also associated with repeat expansion. In contrast, in haplogroup C, there
was a tendency towards contraction in both paternal and maternal transmission.
Stable transmissions or contractions have been observed similarly in some Cretan
families with late onset HD (Tzagournissakis, Fesdjian, Shashidharan, & Plaitakis,
1995). There is, however, no haplotype data of these families, so we cannot directly
compare them with our results. Differences in the intergenerational instability in
56
different haplotypes is probably caused by variable DNA sequence elements that
either stabilize or destabilize the CAG repeat. It is likely that differences in the
instability of paternal and maternal transmission reflect the gender differences in
germ cell generation.
6.4 Evaluation of the research and future prospects
Samples from EOPD patients were collected nationwide from those that possessed
the right to reimbursement of medication. About 40.9% of the patients who
received the invitation letter volunteered to participate in the study (Ylikotila et al.,
2015). It is possible that there may have been a slight bias towards patients that
were in better condition and lived closer to medical centers. The controls consisted
of anonymous blood donors (Meinilä, Finnilä, & Majamaa, 2001). The mean age
of the controls was 40 years, being a few years younger than the mean age at onset
of PD among the patients (46.8 yrs). At the time of the blood withdrawal, the
controls were neurologically healthy, but it is possible that some of them could
develop PD later in their life. Nonetheless, they do represent the general population
in terms of the frequencies of different variants. The genetics of the Finnish
population is regionally variable. We have taken this into account by choosing
population controls from multiple geographical areas that represent the areas in
which the patients were living. The POLG1 gene was screened only for selected
variants and sequenced in 32 patients. Therefore, we may have missed some of the
variants present in our subjects. We compared the frequencies of most of the
POLG1 variants in PD patients against population frequencies readily available in
the literature. Only some of the SNPs were screened in the 403 population controls,
so the information about combinations of the different variants in controls was
limited. We used in silico methods to evaluate the pathogenicity of those variants
that were not previously reported. These are, however, only predictions and cannot
be considered as definite proof of pathogenicity. Samples from HD patients were
collected retrospectively and consisted of samples that had remained in the
diagnostic laboratories after mutation analysis. The length of the HTT CAG repeat
was not determined in controls, so we could not compare the CAG length
distribution in different haplogroups.
We found heterozygous GBA mutations both among PD patients and controls.
Our controls were anonymous blood donors and, hence, it was not possible to
evaluate them clinically. If we had had access to national biobank databases, it
would have been possible to track subjects with heterozygous GBA mutations who
57
do not present with PD. Then, clinical examinations could be performed, or their
clinical records could be viewed to see if their phenotypes differed from that of
individuals without GBA mutations. The mutations found so far in Finnish PD
patients explain only a small fraction of familial PD or EOPD. The Finnish
population differs genetically from other European populations, and therefore
population specific research data is needed. Clarifying the genetic background in
Finnish PD patients would help when planning genetic diagnostic testing to
determine on which areas to concentrate. Many of the mutations found in other
populations have not been found in Finnish patients but typical Finnish PD
mutations are yet to be revealed. WES could be a suitable tool to search for potential
PD mutations in the Finnish population. Furthermore, the distribution of HTT CAG
repeat lengths in the Finnish population is not known. Determining the proportion
of intermediate alleles or alleles with reduced penetration would, however, be
essential in order to predict the rate of new mutations in the population. Our HD
research was retrospective; a prospective study would provide better information
about the genotype-phenotype correlation.
This study concentrated on genotyping risk variants of Parkinson’s disease and
Huntington’s disease. Attempts were made to find novel risk variants of PD using
WES. However, we only managed to scratch the surface in this project. Next
generation sequencing (NGS) techniques like WES could be applied to find more
possible risk variants in both known and novel risk genes. A biochemical
characterization of different variants could be made using cell cultures or animal
models. Understanding the biochemical pathways that are disrupted or changed
could be crucial in discovering novel treatments for these devastating diseases.
With prospective studies of HD, it could be possible to investigate if differences in
the clinical haplotype, e.g. age of onset or motor symptoms, can be detected in the
various haplogroups.
58
59
7 Conclusions
We investigated the genetic factors affecting the risk of PD and HD in Finnish
patients. We found both similarities and differences compared to other European
populations.
1. POLG1 variants are not a common cause of PD. The role of POLG1 variants
in PD is, however, supported by the identification of compound heterozygous
variants found in patients, and the elevated frequency of PD among siblings.
The POLG1 CAG repeat variants other than the common 10Q were
significantly more frequent in EOPD patients than in controls. This could mean
that the non-10Q variants increase the risk of PD or act as a marker for a nearby
PD risk allele.
2. The p.L444P variant in GBA increases the risk of PD. Other variants were
investigated including p.L302P in SMPD1, p.R1441C/G/H in LRRK2,
p.G2019S in LRRK2, p.S59L in CHCHD10 or p.G66V in CHCHD10 were not
found in our patients or controls suggesting that they are rare or even absent in
Finnish population. Five rare variants in LRRK2 and SMPD1 were detected
that might contribute to PD. No association of the MAPT haplotype H1 with
PD could be detected in our study.
3. The HTT haplogroup A, which has been associated with Huntington’s disease,
was less frequent in the Finnish population than in European populations in
general, explaining the lower incidence of HD in Finland. Paternal
transmissions were more prone to expansions, whereas contraction or stable
transmissions were more common in maternal cases. The HTT haplogroups
affected significantly the stability of the transmissions.
60
61
References
Aharon-Peretz, J., Rosenbaum, H., & Gershoni-Baruch, R. (2004). Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med, 351(19), 1972-1977. doi:10.1056/NEJMoa033277
Anvret, A., Westerlund, M., Sydow, O., Willows, T., Lind, C., Galter, D., & Belin, A. C. (2010). Variations of the CAG trinucleotide repeat in DNA polymerase gamma (POLG1) is associated with Parkinson’s disease in Sweden. Neurosci Lett. 485(2):117-120 doi://doi.org/10.1016/j.neulet.2010.08.082
Auranen, M., Ylikallio, E., Shcherbii, M., Paetau, A., Kiuru-Enari, S., Toppila, J. P., & Tyynismaa, H. (2015). CHCHD10 variant p.(Gly66Val) causes axonal Charcot-Marie-Tooth disease. Neurology. Genetics, 1(1), e1. doi:10.1212/NXG.0000000000000003
Autere, J. M., Moilanen, J. S., Myllylä, V. V., & Majamaa, K. (2000). Familial aggregation of Parkinson's disease in a Finnish population. Journal of Neurology, Neurosurgery & Psychiatry, 69(1), 107-109. doi:10.1136/jnnp.69.1.107
Autere, J., Moilanen, J. S., Finnilä, S., Soininen, H., Mannermaa, A., Hartikainen, P., . . . Majamaa, K. (2004). Mitochondrial DNA polymorphisms as risk factors for Parkinson's disease and Parkinson's disease dementia. Human Genetics, 115(1), 29-35. doi:10.1007/s00439-004-1123-9
Aziz, N. A., van Belzen, M. J., Coops, I. D., Belfroid, R. D. M., & Roos, R. A. C. (2011). Parent-of-origin differences of mutant HTT CAG repeat instability in Huntington's disease. European Journal of Medical Genetics, 54(4), 413. doi:10.1016/j.ejmg.2011.04.002
Bae, J. R., & Lee, B. D. (2015). Function and dysfunction of leucine-rich repeat kinase 2 (LRRK2): Parkinson's disease and beyond. BMB Reports, 48(5), 243-248. doi:10.5483/BMBRep.2015.48.5.032
Baine, F. K., Krause, A., & Greenberg, L. J. (2016). The frequency of Huntington disease and Huntington disease-like 2 in the South African population. Neuroepidemiology, 46(3), 198-202. doi:10.1159/000444020
Balafkan, N., Tzoulis, C., Müller, B., Haugarvoll, K., Tysnes, O., Larsen, J. P., & Bindoff, L. A. (2012). Number of CAG repeats in POLG1 and its association with Parkinson disease in the Norwegian population. Mitochondrion, 12(6), 640-643. doi:10.1016/j.mito.2012.08.004
Banerjee, R., Starkov, A. A., Beal, M. F., & Thomas, B. (2009). Mitochondrial dysfunction in the limelight of Parkinson's disease pathogenesis. Biochimica Et Biophysica Acta, 1792(7), 651.
Bannwarth, S., Ait-El-Mkadem, S., Chaussenot, A., Genin, E. C., Lacas-Gervais, S., Fragaki, K., . . . Paquis-Flucklinger, V. (2014). A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain: A Journal of Neurology, 137(Pt 8), 2329-2345. doi:10.1093/brain/awu138
Beavan, M. S., & Schapira, A. H. V. (2013). Glucocerebrosidase mutations and the pathogenesis of Parkinson disease. Annals of Medicine, 45(8), 511-521. doi:10.3109/07853890.2013.849003
62
Belin, A., Westerlund, M., Sydow, O., Lundstromer, K., Hakansson, A., Nissbrandt, H., . . . Galter, D. (2006). Leucine-rich repeat kinase 2 (LRRK2) mutations in a swedish parkinson cohort and a healthy nonagenarian. Movement Disorders : Official Journal of the Movement Disorder Society, 21(10), 1731.
Benamer, H. T. S., & de Silva, R. (2010). LRRK2 G2019S in the North African population: A review. European Neurology, 63(6), 321-325. doi:10.1159/000279653
Bendl, J., Stourac, J., Salanda, O., Pavelka, A., Wieben, E. D., Zendulka, J., . . . Damborsky, J. (2014). PredictSNP: Robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Computational Biology, 10(1), e1003440. doi:10.1371/journal.pcbi.1003440
Betarbet, R., Sherer, T. B., MacKenzie, G., Garcia-Osuna, M., Panov, A. V., & Greenamyre, J. T. (2000). Chronic systemic pesticide exposure reproduces features of parkinson's disease. Nature Neuroscience, 3(12), 1301-1306. doi:10.1038/81834
Bindoff, L. A., Birch-Machin, M. A., Cartlidge, N. E., Parker, W. D., & Turnbull, D. M. (1991). Respiratory chain abnormalities in skeletal muscle from patients with Parkinson's disease. Journal of the Neurological Sciences, 104(2), 203-208.
Blanckenberg, J., Bardien, S., Glanzmann, B., Okubadejo, N. U., & Carr, J. A. (2013). The prevalence and genetics of Parkinson's disease in sub-Saharan Africans J Neurol Sci. 335(1-2):22-5. doi://doi.org/10.1016/j.jns.2013.09.010
Blin, P., Dureau-Pournin, C., Foubert-Samier, A., Grolleau, A., Corbillon, E., Jové, J., . . . Moore, N. (2015). Parkinson's disease incidence and prevalence assessment in France using the national healthcare insurance database. European Journal of Neurology, 22(3), 464-471. doi:10.1111/ene.12592
Bonifati, V., Fabrizio, E., Vanacore, N., De Mari, M., & Meco, G. (1995). Familial Parkinson's disease: A clinical genetic analysis. The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques, 22(4), 272-279.
Bonifati, V., Rizzu, P., van Baren, M. J., Schaap, O., Breedveld, G. J., Krieger, E., . . . Heutink, P. (2003). Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science (New York, N.Y.), 299(5604), 256-259. doi:10.1126/science.1077209
Brockmann, K., & Berg, D. (2014). The significance of GBA for parkinson's disease. Journal of Inherited Metabolic Disease, 37(4), 643. doi:10.1007/s10545-014-9714-7
Chartier-Harlin, M., Dachsel, J. C., Vilariño-Güell, C., Lincoln, S. J., Leprêtre, F., Hulihan, M. M., . . . Farrer, M. J. (2011). Translation initiator EIF4G1 mutations in familial Parkinson disease. American Journal of Human Genetics, 89(3), 398-406. doi:10.1016/j.ajhg.2011.08.009
Chen, R. C., Chang, S. F., Su, C. L., Chen, T. H., Yen, M. F., Wu, H. M., . . . Liou, H. H. (2001). Prevalence, incidence, and mortality of PD: A door-to-door survey in Ilan county, Taiwan. Neurology, 57(9), 1679-1686.
Chen, Y., Chen, W., Lin, X., Zhang, Q., Cai, J., Liou, C., & Wang, N. (2015). Mitochondrial DNA haplogroups and the risk of sporadic Parkinson's disease in Han Chinese. Chinese Medical Journal, 128(13), 1748-1754. doi:10.4103/0366-6999.159348
63
Cookson, M. (2015). LRRK2 pathways leading to neurodegeneration. Current Neurology and Neuroscience Reports, 15(7), 1-10. doi:10.1007/s11910-015-0564-y
Coxhead, J., Kurzawa-Akanbi, M., Hussain, R., Pyle, A., Chinnery, P., & Hudson, G. (2016). Somatic mtDNA variation is an important component of Parkinson's disease. Neurobiology of Aging, 38, 217.e-217.e6. doi:10.1016/j.neurobiolaging.2015.10.036
Craven, L., Alston, C. L., Taylor, R. W., & Turnbull, D. M. (2017). Recent advances in mitochondrial disease. Annual Review of Genomics and Human Genetics, 18, 257-275. doi:10.1146/annurev-genom-091416-035426
Dagan, E., Schlesinger, I., Ayoub, M., Mory, A., Nassar, M., Kurolap, A., . . . Gershoni-Baruch, R. (2015). The contribution of Niemann-Pick SMPD1 mutations to Parkinson disease in Ashkenazi Jews. Parkinsonism & Related Disorders, 21(9), 1067-1071. doi:10.1016/j.parkreldis.2015.06.016
Dahl, N., Hillborg, P. O., & Olofsson, A. (1993). Gaucher disease (Norrbottnian type III): Probable founders identified by genealogical and molecular studies. Human Genetics, 92(5), 513-515. doi:10.1007/bf00216461
Davidzon, G., Greene, P., Mancuso, M., Klos, K. J., Ahlskog, J. E., Hirano, M., & DiMauro, S. (2006). Early-onset familial parkinsonism due to POLG mutations. Annals of Neurology, 59(5), 859-862. doi:10.1002/ana.20831
Dolgacheva, L. P., Berezhnov, A. V., Fedotova, E. I., Zinchenko, V. P., & Abramov, A. Y. (2019). Role of DJ-1 in the mechanism of pathogenesis of Parkinson's disease. Journal of Bioenergetics and Biomembranes, 51(3), 175-188. doi:10.1007/s10863-019-09798-4
Duncan, G. W., Khoo, T. K., Coleman, S. Y., Brayne, C., Yarnall, A. J., O'Brien, J. T., . . . Burn, D. J. (2014). The incidence of Parkinson's disease in the north-east of England. Age and Ageing, 43(2), 257-263. doi:10.1093/ageing/aft091
Durcan, T. M., & Fon, E. A. (2015). The three 'P's of mitophagy: PARKIN, PINK1, and post-translational modifications. Genes & Development, 29(10), 989-999. doi:10.1101/gad.262758.115
Eerola, J., Luoma, P. T., Peuralinna, T., Scholz, S., Paisan-Ruiz, C., Suomalainen, A., . . . Tienari, P. J. (2010). POLG1 polyglutamine tract variants associated with Parkinson's disease. Neuroscience Letters, 477(1), 1-5. doi:10.1016/j.neulet.2010.04.021
Ekstrand, M. I., Terzioglu, M., Galter, D., Zhu, S., Hofstetter, C., Lindqvist, E., . . . Larsson, N. G. (2007). Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proceedings of the National Academy of Sciences of the United States of America, 104(4), 1325-1330. doi:0605208103 [pii]
Elbaz, A., Grigoletto, F., Baldereschi, M., Breteler, M. M., Manubens-Bertran, J. M., Lopez-Pousa, S., . . . Rocca, W. A. (1999). Familial aggregation of Parkinson's disease: A population-based case-control study in Europe. EUROPARKINSON study group. Neurology, 52(9), 1876-1882. doi:10.1212/wnl.52.9.1876
Emelyanov, A. K., Usenko, T. S., Tesson, C., Senkevich, K. A., Nikolaev, M. A., Miliukhina, I. V., . . . Pchelina, S. N. (2018). Mutation analysis of Parkinson's disease genes in a Russian data set. Neurobiology of Aging, 71, 267.e-267.e10. doi:10.1016/j.neurobiolaging.2018.06.027
64
Fearnley, J. M., & Lees, A. J. (1991). Ageing and Parkinson's disease: Substantia nigra regional selectivity. Brain: A Journal of Neurology, 114 ( Pt 5), 2283-2301.
Federico, A., Cardaioli, E., Da Pozzo, P., Formichi, P., Gallus, G. N., & Radi, E. (2012). Mitochondria, oxidative stress and neurodegeneration. Journal of the Neurological Sciences, 322(1), 254-262. doi:10.1016/j.jns.2012.05.030
Flønes, I. H., Fernandez-Vizarra, E., Lykouri, M., Brakedal, B., Skeie, G. O., Miletic, H., . . . Tzoulis, C. (2017). Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage. Acta Neuropathologica, , 1-17. doi:10.1007/s00401-017-1794-7
Funayama, M., Ohe, K., Amo, T., Furuya, N., Yamaguchi, J., Saiki, S., . . . Hattori, N. (2015). CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: A genome-wide linkage and sequencing study. The Lancet. Neurology, 14(3), 274-282. doi:10.1016/S1474-4422(14)70266-2
Gan-Or, Z., Orr-Urtreger, A., Alcalay, R. N., Bressman, S., Giladi, N., & Rouleau, G. A. (2015). The emerging role of SMPD1 mutations in parkinson's disease: Implications for future studies. Parkinsonism Relat Disord. 21(10):1294-1295 doi://doi.org/10.1016/j.parkreldis.2015.08.018
Gan-Or, Z., Ozelius, L. J., Bar-Shira, A., Saunders-Pullman, R., Mirelman, A., Kornreich, R., . . . Orr-Urtreger, A. (2013). The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease. Neurology, 80(17), 1606-1610. doi:10.1212/WNL.0b013e31828f180e
Gao, F., Yang, J., Wang, D., Li, C., Fu, Y., Wang, H., . . . Zhang, J. (2017). Mitophagy in Parkinson's disease: Pathogenic and therapeutic implications. Frontiers in Neurology, 8, 527. doi:10.3389/fneur.2017.00527
Gaweda-Walerych, K., Maruszak, A., Safranow, K., Bialecka, M., Klodowska-Duda, G., Czyzewski, K., . . . Zekanowski, C. (2008). Mitochondrial DNA haplogroups and subhaplogroups are associated with Parkinson’s disease risk in a Polish PD cohort. Journal of Neural Transmission, 115(11), 1521-1526. doi:10.1007/s00702-008-0121-9
Ghezzi, D., Marelli, C., Achilli, A., Goldwurm, S., Pezzoli, G., Barone, P., . . . Zeviani, M. (2005). Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson's disease in Italians. European Journal of Human Genetics, 13(6), 748-752. doi:10.1038/sj.ejhg.5201425
Giachin, G., Bouverot, R., Acajjaoui, S., Pantalone, S., & Soler-López, M. (2016). Dynamics of human mitochondrial complex I assembly: Implications for neurodegenerative diseases. Frontiers in Molecular Biosciences, 3, 43. doi:10.3389/fmolb.2016.00043
Gibb, W. R., & Lees, A. J. (1988). The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. Journal of Neurology, Neurosurgery, and Psychiatry, 51(6), 745-752.
Gordon, P. H., Mehal, J. M., Holman, R. C., Bartholomew, M. L., Cheek, J. E., & Rowland, A. S. (2015). Incidence and prevalence of Parkinson's disease among Navajo people living in the Navajo nation. Movement Disorders, 30(5), 714-720. doi:10.1002/mds.26147
65
Gövert, F., & Schneider, S. A. (2013). Huntington's disease and Huntington's disease-like syndromes: An overview. Current Opinion in Neurology, 26(4), 420-427. doi:10.1097/WCO.0b013e3283632d90
Gui, Y., Xu, Z., Lv, W., Liu, H., Zhao, J., & Hu, X. (2012). Association of mitochondrial DNA polymerase γ gene POLG1 polymorphisms with parkinsonism in Chinese populations. PloS One, 7(12), e50086. doi:10.1371/journal.pone.0050086
Gusella, J. F., Wexler, N. S., Conneally, P. M., Naylor, S. L., Anderson, M. A., Tanzi, R. E., . . . Sakaguchi, A. Y. (1983). A polymorphic DNA marker genetically linked to Huntington's disease. Nature, 306(5940), 234-238.
Hakonen, A. H., Davidzon, G., Salemi, R., Bindoff, L. A., Van Goethem, G., Dimauro, S., . . . Suomalainen, A. (2007). Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders. European Journal of Human Genetics: EJHG, 15(7), 779-783. doi:10.1038/sj.ejhg.5201831
Hakonen, A. H., Heiskanen, S., Juvonen, V., Lappalainen, I., Luoma, P. T., Rantamäki, M., . . . Suomalainen, A. (2005). Mitochondrial DNA polymerase W748S mutation: A common cause of autosomal recessive ataxia with ancient European origin. The American Journal of Human Genetics, 77(3), 430-441. doi:10.1086/444548
Havulinna, A. S., Tienari, P. J., Marttila, R. J., Martikainen, K. K., Eriksson, J. G., Taskinen, O., . . . Karvonen, M. (2008). Geographical variation of medicated parkinsonism in Finland during 1995 to 2000. Movement Disorders, 23(7), 1024-1031. doi:10.1002/mds.22024
Heinz, S., Freyberger, A., Lawrenz, B., Schladt, L., Schmuck, G., & Ellinger-Ziegelbauer, H. (2017). Mechanistic investigations of the mitochondrial complex I inhibitor rotenone in the context of pharmacological and safety evaluation. Scientific Reports, 7, 45465. doi:10.1038/srep45465
Hillen, H. S., Temiakov, D., & Cramer, P. (2018). Structural basis of mitochondrial transcription. Nature Structural & Molecular Biology, 25(9), 754-765. doi:10.1038/s41594-018-0122-9
Hudson, G., Nalls, M., Evans, J., Breen, D., Winder-Rhodes, S., Morrison, K., . . . Chinnery, P. (2013). Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. Neurology, 80(22), 2042-2048. doi:10.1212/WNL.0b013e318294b434
Hudson, G., Tiangyou, W., Stutt, A., Eccles, M., Robinson, L., Burn, D. J., & Chinnery, P. F. (2009). No association between common POLG1 variants and sporadic idiopathic Parkinson's disease. Movement Disorders: Official Journal of the Movement Disorder Society, 24(7), 1092-1094. doi:10.1002/mds.22310
Hughes, A. J., Daniel, S. E., & Lees, A. J. (2001). Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease. Neurology, 57(8), 1497-1499.
Huntington, G. (1872). On chorea. The Medical and Surgical Reporter: A Weekly Journal, 26(15), 317–321.
66
Ibrahim, N., Kusmirek, J., Struck, A. F., Floberg, J. M., Perlman, S. B., Gallagher, C., & Hall, L. T. (2016). The sensitivity and specificity of F-DOPA PET in a movement disorder clinic. American Journal of Nuclear Medicine and Molecular Imaging, 6(1), 102-109.
Jansen, I. E., Gibbs, J. R., Nalls, M. A., Price, T. R., Lubbe, S., van Rooij, J., . . . Sharma, M. (2017). Establishing the role of rare coding variants in known Parkinson's disease risk loci. Neurobiology of Aging, 59, 220.e1-220.e18. doi:10.1016/j.neurobiolaging. 2017.07.009
Kaasinen, V., Hietala, M., & Kuoppamäki, M. (2015). [Parkinson's disease associated with a mutation in the PARK2 gene]. Duodecim; Laaketieteellinen Aikakauskirja, 131(12), 1187-1190.
Kalia, L. V., & Lang, A. E. (2015). Parkinson's disease. Lancet. 386(9996):896-912. doi://doi.org/10.1016/S0140-6736(14)61393-3
Kang, I., Chu, C. T., & Kaufman, B. A. (2018). The mitochondrial transcription factor TFAM in neurodegeneration: Emerging evidence and mechanisms. FEBS Letters, 592(5), 793-811. doi:10.1002/1873-3468.12989
Kasiviswanathan, R., & Copeland, W. C. (2011). Biochemical analysis of the G517V POLG variant reveals wild-type like activity. Mitochondrion, 11(6), 929-934. doi:10.1016/j.mito.2011.08.003
Kay, C., Collins, J. A., Skotte, N. H., Southwell, A. L., Warby, S. C., Caron, N. S., . . . Hayden, M. R. (2015). Huntingtin haplotypes provide prioritized target panels for allele-specific silencing in Huntington disease patients of European ancestry. Molecular Therapy : The Journal of the American Society of Gene Therapy, 23(11), 1759-1771. doi:10.1038/mt.2015.128
Keller, M. F., Saad, M., Bras, J., Bettella, F., Nicolaou, N., Simón-Sánchez, J., . . . Nalls, M. A. (2012). Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. Human Molecular Genetics, 21(22), 4996-5009. doi:10.1093/hmg/dds335
Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., . . . Shimizu, N. (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 392(6676), 605-608. doi:10.1038/33416
Komulainen, T., Hinttala, R., Kärppä, M., Pajunen, L., Finnilä, S., Tuominen, H., . . . Uusimaa, J. (2010). POLG1 p.R722H mutation associated with multiple mtDNA deletions and a neurological phenotype. BMC Neurology, 10, 29. doi:10.1186/1471-2377-10-29
Kuopio, A. M., Marttila, R. J., Helenius, H., & Rinne, U. K. (1999). Changing epidemiology of Parkinson's disease in southwestern Finland. Neurology, 52(2), 302-308.
Kuopio, A. -., Marttila, R. J., Helenius, H., & Rinne, U. K. (2001). Familial occurrence of parkinson's disease in a community-based case-control study. Parkinsonism & Related Disorders, 7(4), 297-303.
Langston, J. W., Ballard, P., Tetrud, J. W., & Irwin, I. (1983). Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science (New York, N.Y.), 219(4587), 979-980.
67
Leroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., . . . Polymeropoulos, M. H. (1998). The ubiquitin pathway in Parkinson's disease. Nature, 395(6701), 451-452. doi:10.1038/26652
Lesage, S., Anheim, M., Condroyer, C., Pollak, P., Durif, F., Dupuits, C., . . . Brice, A. (2011). Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease. Human Molecular Genetics, 20(1), 202-210. doi:10.1093/hmg/ddq454
Lesage, S., Dürr, A., Tazir, M., Lohmann, E., Leutenegger, A., Janin, S., . . . Brice, A. (2006). LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med, 354(4), 422-423. doi:10.1056/NEJMc055540
Li, H., Ham, A., Ma, T. C., Kuo, S., Kanter, E., Kim, D., . . . Tang, G. (2018). Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations. Autophagy, doi:10.1080/15548627.2018.1509818
Li, K., Tang, B., Yang, N., Kang, J., Liu, Z., Liu, R., . . . Guo, J. (2015). Association study between SMPD1 p.L302P and sporadic Parkinson's disease in ethnic Chinese population. International Journal of Clinical and Experimental Medicine, 8(8), 13869-13873.
Li, N., Ragheb, K., Lawler, G., Sturgis, J., Rajwa, B., Melendez, J. A., & Robinson, J. P. (2003). Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. The Journal of Biological Chemistry, 278(10), 8516-8525. doi:10.1074/jbc.M210432200
Luoma, P. T., Eerola, J., Ahola, S., Hakonen, A. H., Hellström, O., Kivistö, K. T., . . . Suomalainen, A. (2007). Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease. Neurology, 69(11), 1152-1159. doi:10.1212/01.wnl.0000276955.23735.eb
Luoma, P. T., Luo, N., Löscher, W. N., Farr, C. L., Horvath, R., Wanschitz, J., . . . Suomalainen, A. (2005). Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome. Human Molecular Genetics, 14(14), 1907-1920. doi:10.1093/hmg/ddi196
Luoma, P. T., Melberg, A., Rinne, J. O., Kaukonen, J. A., Nupponen, N. N., Chalmers, R. M., . . . Suomalainen, A. (2004). Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: Clinical and molecular genetic study. Lancet (London, England), 364(9437), 875-882. doi:10.1016/S0140-6736(04)16983-3
MacDonald, M. E., Novelletto, A., Lin, C., Tagle, D., Barnes, G., Bates, G., . . . Myers, R. (1992). The Huntington's disease candidate region exhibits many different haplotypes. Nature Genetics, 1(2), 99-103. doi:10.1038/ng0592-99
MacDonald, M. E., Ambrose, C. M., Duyao, M. P., Myers, R. H., Lin, C., Srinidhi, L., . . . Harper, P. S. (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell, 72(6), 971-983. doi:10.1016/0092-8674(93)90585-E
68
Mao, C., Yang, J., Wang, H., Zhang, S., Yang, Z., Luo, H., . . . Xu, Y. (2017). SMPD1 variants in Chinese Han patients with sporadic Parkinson's disease. Parkinsonism & Related Disorders, 34, 59-61. doi:10.1016/j.parkreldis.2016.10.014
Marder, K., Tang, M. X., Mejia, H., Alfaro, B., Côté, L., Louis, E., . . . Mayeux, R. (1996). Risk of Parkinson's disease among first-degree relatives: A community-based study. Neurology, 47(1), 155-160. doi:10.1212/wnl.47.1.155
Marder, K., Wang, Y., Alcalay, R., Mejia-Santana, H., Tang, M., Lee, A., . . . Bressman, S. (2015). Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 consortium. Neurology, 85(1), 89-95. doi:10.1212/WNL. 0000000000001708
Martikainen, M. H., Päivärinta, M., Hietala, M., & Kaasinen, V. (2015). Clinical and imaging findings in Parkinson disease associated with the A53E SNCA mutation. Neurology. Genetics, 1(4), e27. doi:10.1212/NXG.0000000000000027
Meinilä, M., Finnilä, S., & Majamaa, K. (2001). Evidence for mtDNA admixture between the Finns and the Saami. Human Heredity, 52(3), 160-170. doi:10.1159/000053372
Moore, D. J., Zhang, L., Troncoso, J., Lee, M. K., Hattori, N., Mizuno, Y., . . . Dawson, V. L. (2005). Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Human Molecular Genetics, 14(1), 71-84. doi:10.1093/hmg/ddi007
Narendra, D. P., Jin, S. M., Tanaka, A., Suen, D., Gautier, C. A., Shen, J., . . . Youle, R. J. (2010). PINK1 is selectively stabilized on impaired mitochondria to activate parkin. PLoS Biology, 8(1), e1000298. doi:10.1371/journal.pbio.1000298
Naviaux, R. K., & Nguyen, K. V. (2004). POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Annals of Neurology, 55(5), 706-712. doi:10.1002/ana.20079
Nikoskelainen, E. K., Marttila, R. J., Huoponen, K., Juvonen, V., Lamminen, T., Sonninen, P., & Savontaus, M. L. (1995). Leber's "plus": Neurological abnormalities in patients with Leber's hereditary optic neuropathy. Journal of Neurology, Neurosurgery, and Psychiatry, 59(2), 160-164.
Obeso, J. A., Stamelou, M., Goetz, C. G., Poewe, W., Lang, A. E., Weintraub, D., . . . Stoessl, A. J. (2017). Past, present, and future of Parkinson's disease: A special essay on the 200th anniversary of the shaking palsy. Movement Disorders: Official Journal of the Movement Disorder Society, 32(9), 1264-1310. doi:10.1002/mds.27115
Palin, E. J. H., Lesonen, A., Farr, C. L., Euro, L., Suomalainen, A., & Kaguni, L. S. (2010). Functional analysis of H. sapiens DNA polymerase gamma spacer mutation W748S with and without common variant E1143G. Biochimica Et Biophysica Acta, 1802(6), 545-551. doi:10.1016/j.bbadis.2010.02.003
Parker, W. D., Boyson, S. J., & Parks, J. K. (1989). Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Annals of Neurology, 26(6), 719-723. doi:10.1002/ana.410260606
Parkinson, J. (1817). An essay on the shaking palsy. London: Whittingham and Rowland for Sherwood, Neely, and Jones.
69
Pasanen, P., Myllykangas, L., Siitonen, M., Raunio, A., Kaakkola, S., Lyytinen, J., . . . Paetau, A. (2014). Novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology. Neurobiology of Aging, 35(9), 2180.e-5. doi:10.1016/j.neurobiolaging.2014.03.024
Pasanen, P., Palin, E., Pohjolan-Pirhonen, R., Pöyhönen, M., Rinne, J. O., Päivärinta, M., . . . Myllykangas, L. (2017). SNCA mutation p.Ala53Glu is derived from a common founder in the Finnish population. Neurobiology of Aging, 50, 168.e-168.e8. doi:10.1016/j.neurobiolaging.2016.10.014
Payami, H., Larsen, K., Bernard, S., & Nutt, J. (1994). Increased risk of Parkinson's disease in parents and siblings of patients. Annals of Neurology, 36(4), 659-661. doi:10.1002/ana.410360417
Penttilä, S., Jokela, M., Bouquin, H., Saukkonen, A. M., Toivanen, J., & Udd, B. (2015). Late onset spinal motor neuronopathy is caused by mutation in CHCHD10. Annals of Neurology, 77(1), 163-172. doi:10.1002/ana.24319
Perier, C., & Vila, M. (2012). Mitochondrial biology and Parkinson's disease. Cold Spring Harbor Perspectives in Medicine, 2(2), a009332. doi:10.1101/cshperspect.a009332
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., . . . Nussbaum, R. L. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science (New York, N.Y.), 276(5321), 2045-2047.
Postuma, R. B., Berg, D., Stern, M., Poewe, W., Olanow, C. W., Oertel, W., . . . Deuschl, G. (2015). MDS clinical diagnostic criteria for Parkinson's disease. Movement Disorders: Official Journal of the Movement Disorder Society, 30(12), 1591-1601. doi:10.1002/mds.26424
Pulkes, T., Choubtum, L., Chitphuk, S., Thakkinstian, A., Pongpakdee, S., Kulkantrakorn, K., . . . Boonkongchuen, P. (2014). Glucocerebrosidase mutations in Thai patients with Parkinson's disease. Parkinsonism & Related Disorders, 20(9), 986-991. doi:10.1016/j.parkreldis.2014.06.007
Rahman, S., & Copeland, W. C. (2018). POLG-related disorders and their neurological manifestations. Nature Reviews. Neurology, doi:10.1038/s41582-018-0101-0
Ramirez, A., Heimbach, A., Gründemann, J., Stiller, B., Hampshire, D., Cid, L. P., . . . Kubisch, C. (2006). Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nature Genetics, 38(10), 1184-1191. doi:10.1038/ng1884
Ran, C., Brodin, L., Forsgren, L., Westerlund, M., Ramezani, M., Gellhaar, S., . . . Belin, A. C. (2016). Strong association between glucocerebrosidase mutations and Parkinson's disease in Sweden. Neurobiology of Aging, 45, 212.e-212.e11. doi:10.1016/ j.neurobiolaging.2016.04.022
Remes, A. M., Hinttala, R., Kärppä, M., Soini, H., Takalo, R., Uusimaa, J., & Majamaa, K. (2008). Parkinsonism associated with the homozygous W748S mutation in the POLG1 gene. Parkinsonism & Related Disorders, 14(8), 652-654. doi:10.1016/ j.parkreldis.2008.01.009
70
Rempe, T., Kuhlenbäumer, G., Krüger, S., Biskup, S., Matschke, J., Hagel, C., . . . van Eimeren, T. (2016). Early-onset parkinsonism due to compound heterozygous POLG mutations. Parkinsonism & Related Disorders, 29, 135-137. doi:10.1016/j.parkreldis. 2016.04.020
Requejo-Aguilar, R., Lopez-Fabuel, I., Jimenez-Blasco, D., Fernandez, E., Almeida, A., & Bolaños, J. P. (2015). DJ1 represses glycolysis and cell proliferation by transcriptionally up-regulating Pink1. The Biochemical Journal, 467(2), 303-310. doi:10.1042/BJ20141025
Rizzo, G., Copetti, M., Arcuti, S., Martino, D., Fontana, A., & Logroscino, G. (2016). Accuracy of clinical diagnosis of Parkinson disease: A systematic review and meta-analysis. Neurology, 86(6), 566-576. doi:10.1212/WNL.0000000000002350
Robak, L. A., Jansen, I. E., van Rooij, J., Uitterlinden, A. G., Kraaij, R., Jankovic, J., . . . Shulman, J. M. (2017). Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. Brain: A Journal of Neurology, 140(12), 3191-3203. doi:10.1093/brain/awx285
Rosas, H. D., Chen, Y. I., Doros, G., Salat, D. H., Chen, N., Kwong, K. K., . . . Hersch, S. M. (2012). Alterations in brain transition metals in Huntington disease: An evolving and intricate story. Archives of Neurology, 69(7), 887-893. doi:10.1001/archneurol.2011.2945
Ross, C. A., Kronenbuerger, M., Duan, W., & Margolis, R. L. (2017). Mechanisms underlying neurodegeneration in Huntington disease: Applications to novel disease-modifying therapies. Handbook of Clinical Neurology, 144, 15-28. doi:10.1016/B978-0-12-801893-4.00002-X
Ross, C. A., Aylward, E. H., Wild, E. J., Langbehn, D. R., Long, J. D., Warner, J. H., . . . Tabrizi, S. J. (2014). Huntington disease: Natural history, biomarkers and prospects for therapeutics. Nature Reviews. Neurology, 10(4), 204. doi:10.1038/nrneurol.2014.24
Rovio, A. T., Marchington, D. R., Donat, S., Schuppe, H. C., Abel, J., Fritsche, E., . . . Jacobs, H. T. (2001). Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nature Genetics, 29(3), 261-262. doi:10.1038/ng759
Schapira, A. H. V., Cooper, J. M., Dexter, D., Jenner, P., Clark, J. B., & Marsden, C. D. (1989). Mitochondrial complex I deficiency in Parkinson's disease. The Lancet, 333(8649), 1269. doi:10.1016/S0140-6736(89)92366-0
Schapira, A. H. V. (2015). Glucocerebrosidase and Parkinson disease: Recent advances. Molecular and Cellular Neurosciences, 66(Pt A), 37-42. doi:10.1016/j.mcn. 2015.03.013
Schuchman, E. (2007). The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann–Pick disease. Journal of Inherited Metabolic Disease, 30(5), 654-663. doi:10.1007/s10545-007-0632-9
Semchuk, K. M., Love, E. J., & Lee, R. G. (1993). Parkinson's disease: A test of the multifactorial etiologic hypothesis. Neurology, 43(6), 1173-1180. doi:10.1212/wnl.43.6.1173
71
Siddiqui, I. J., Pervaiz, N., & Abbasi, A. A. (2016). The Parkinson disease gene SNCA: Evolutionary and structural insights with pathological implication. Scientific Reports, 6, 24475. doi:10.1038/srep24475
Sidransky, E., Nalls, M. A., Aasly, J. O., Aharon-Peretz, J., Annesi, G., Barbosa, E. R., . . . Ziegler, S. G. (2009). Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. The New England Journal of Medicine, 361(17), 1651-1661. doi:10.1056/NEJMoa0901281
Siitonen, A., Nalls, M. A., Hernández, D., Gibbs, J. R., Ding, J., Ylikotila, P., . . . Majamaa, K. (2017). Genetics of early-onset Parkinson's disease in Finland: Exome sequencing and genome-wide association study. Neurobiology of Aging, 53, 195.e-195.e10. doi:10.1016/j.neurobiolaging.2017.01.019
Simon, D. K., Pulst, S. M., Sutton, J. P., Browne, S. E., Beal, M. F., & Johns, D. R. (1999). Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation. Neurology, 53(8), 1787-1793.
Sipilä, J. O. T., Hietala, M., Siitonen, A., Päivärinta, M., & Majamaa, K. (2015). Epidemiology of huntington's disease in Finland doi://doi.org/10.1016/j.parkreldis. 2014.10.025
Spelbrink, J. N., Toivonen, J. M., Hakkaart, G. A., Kurkela, J. M., Cooper, H. M., Lehtinen, S. K., . . . Jacobs, H. T. (2000). In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. The Journal of Biological Chemistry, 275(32), 24818-24828. doi:10.1074/jbc.M000559200
Squitieri, F., Andrew, S. E., Goldberg, Y. P., Kremer, B., Spence, N., Zeisler, J., . . . Goto, J. (1994). DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence. Human Molecular Genetics, 3(12), 2103-2114.
Sveinsson, O., Halldórsson, S., & Olafsson, E. (2012). An unusually low prevalence of Huntington's disease in Iceland. European Neurology, 68(1), 48-51. doi:10.1159/000337680
Synofzik, M., Schicks, J., Srulijes, K., Schulte, C., Schiele, F., Berg, D., & Schöls, L. (2012). POLG and PEO1 (twinkle) mutations are infrequent in PSP-like atypical parkinsonism: A preliminary screening study. Journal of Neurology, 259(10), 2232-2233. doi:10.1007/s00415-012-6535-1
Szczepanowska, K., & Trifunovic, A. (2017). Origins of mtDNA mutations in ageing. Essays in Biochemistry, 61(3), 325-337. doi:10.1042/EBC20160090
Taira, T., Saito, Y., Niki, T., Iguchi-Ariga, S. M. M., Takahashi, K., & Ariga, H. (2004). DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Reports, 5(2), 213-218. doi:10.1038/sj.embor.7400074
Tambasco, N., Nigro, P., Romoli, M., Prontera, P., Simoni, S., & Calabresi, P. (2016). A53T in a parkinsonian family: A clinical update of the SNCA phenotypes. Journal of Neural Transmission (Vienna, Austria: 1996), 123(11), 1301-1307. doi:10.1007/s00702-016-1578-6
72
Tang, B., Xiong, H., Sun, P., Zhang, Y., Wang, D., Hu, Z., . . . Zhang, Z. (2006). Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease. Human Molecular Genetics, 15(11), 1816-1825. doi:10.1093/hmg/ddl104
Tangamornsuksan, W., Lohitnavy, O., Sruamsiri, R., Chaiyakunapruk, N., Norman Scholfield, C., Reisfeld, B., & Lohitnavy, M. (2018). Paraquat exposure and Parkinson's disease: A systematic review and meta-analysis. Archives of Environmental & Occupational Health, , 1-14. doi:10.1080/19338244.2018.1492894
Thiruchelvam, M., McCormack, A., Richfield, E. K., Baggs, R. B., Tank, A. W., Di Monte, D. A., & Cory-Slechta, D. A. (2003). Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype. European Journal of Neuroscience, 18(3), 589-600. doi:10.1046/j.1460-9568.2003.02781.x
Tiangyou, W., Hudson, G., Ghezzi, D., Ferrari, G., Zeviani, M., Burn, D. J., & Chinnery, P. F. (2006). POLG1 in idiopathic parkinson disease. Neurology, 67(9), 1698-1700. doi:10.1212/01.wnl.0000238963.07425.d5
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., . . . Larsson, N. (2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature, 429(6990), 417-423. doi:10.1038/nature02517
Tzagournissakis, M., Fesdjian, C. O., Shashidharan, P., & Plaitakis, A. (1995). Stability of the huntington disease (CAG)n repeat in a late onset form occurring on the island of Crete. Human Molecular Genetics, 4(12), 2239-2243.
Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., . . . Wood, N. W. (2004). Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science (New York, N.Y.), 304(5674), 1158-1160. doi:10.1126/science.1096284
van der Walt, Joelle M, Nicodemus, K. K., Martin, E. R., Scott, W. K., Scott, B. L., Nance, M. A., . . . Vance, J. M. (2003). Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. The American Journal of Human Genetics, 72(4), 804-811. doi:10.1086/373937
Van Goethem, G., Dermaut, B., Löfgren, A., Martin, J. J., & Van Broeckhoven, C. (2001). Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nature Genetics, 28(3), 211-212. doi:10.1038/90034
Van Goethem, G., Martin, J. J., Dermaut, B., Löfgren, A., Wibail, A., Ververken, D., . . . Van Broeckhoven, C. (2003a). Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Neuromuscular Disorders, 13(2), 133-142. doi:10.1016/S0960-8966(02)00216-X
Van Goethem, G., Schwartz, M., Löfgren, A., Dermaut, B., Van Broeckhoven, C., & Vissing, J. (2003b). Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. European Journal of Human Genetics: EJHG, 11(7), 547-549. doi:10.1038/sj.ejhg.5201002
73
van Swieten, J., & Spillantini, M. G. (2007). Hereditary frontotemporal dementia caused by tau gene mutations. Brain Pathology (Zurich, Switzerland), 17(1), 63-73. doi:10.1111/j.1750-3639.2007.00052.x
Venditti, P., Di Stefano, L., & Di Meo, S. (2013). Mitochondrial metabolism of reactive oxygen species. Mitochondrion, 13(2), 71-82. doi:10.1016/j.mito.2013.01.008
Vilariño-Güell, C., Rajput, A., Milnerwood, A. J., Shah, B., Szu-Tu, C., Trinh, J., . . . Farrer, M. J. (2014). DNAJC13 mutations in Parkinson disease. Human Molecular Genetics, 23(7), 1794-1801. doi:10.1093/hmg/ddt570
Warby, S. C., Visscher, H., Collins, J. A., Doty, C. N., Carter, C., Butland, S. L., . . . Hayden, M. R. (2011). HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia. European Journal of Human Genetics: EJHG, 19(5), 561-566. doi:10.1038/ejhg.2010.229
Warby, S. C., Montpetit, A., Hayden, A. R., Carroll, J. B., Butland, S. L., Visscher, H., . . . Hayden, M. R. (2009). CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup. American Journal of Human Genetics, 84(3), 351-366. doi:10.1016/j.ajhg.2009.02.003
Webb, A., Miller, B., Bonasera, S., Boxer, A., Karydas, A., & Wilhelmsen, K. C. (2008). Role of the tau gene region chromosome inversion in progressive supranuclear palsy, corticobasal degeneration, and related disorders. Archives of Neurology, 65(11), 1473-1478. doi:10.1001/archneur.65.11.1473
Winterthun, S., Ferrari, G., He, L., Taylor, R. W., Zeviani, M., Turnbull, D. M., . . . Bindoff, L. A. (2005). Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations. Neurology, 64(7), 1204-1208. doi:10.1212/01.WNL.0000156516.77696.5A
Wu, R., Lin, C., & Lin, H. (2014). The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease. Neurology, 82(3), 283. doi:10.1212/WNL.0000000000000004
Yan, S., Tu, Z., Liu, Z., Fan, N., Yang, H., Yang, S., . . . Li, X. (2018). A huntingtin knock-in pig model recapitulates features of selective neurodegeneration in Huntington’s disease. Cell, 173(4), 989-1002.e13 doi://doi.org/10.1016/j.cell.2018.03.005
Ylikotila, P., Tiirikka, T., Moilanen, J. S., Kääriäinen, H., Marttila, R., & Majamaa, K. (2015). Epidemiology of early-onset Parkinson's disease in Finland Parkinsonism Relat Disord. 21(8), 938-942. doi://doi.org/10.1016/j.parkreldis.2015.06.003
Zabetian, C. P., Hutter, C. M., Factor, S. A., Nutt, J. G., Higgins, D. S., Griffith, A., . . . Payami, H. (2007). Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease. Annals of Neurology, 62(2), 137-144. doi:10.1002/ana.21157
Zampieri, S., Filocamo, M., Pianta, A., Lualdi, S., Gort, L., Coll, M. J., . . . Dardis, A. (2016). SMPD1 mutation update: Database and comprehensive analysis of published and novel variants. Human Mutation, 37(2), 139-147. doi:10.1002/humu.22923
Zhang, M., Xi, Z., Zinman, L., Bruni, A. C., Maletta, R. G., Curcio, S. A. M., . . . Rogaeva, E. (2015). Mutation analysis of CHCHD10 in different neurodegenerative diseases. Brain: A Journal of Neurology, 138(Pt 9), e380. doi:10.1093/brain/awv082
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Zheng, N., & Shabek, N. (2017). Ubiquitin ligases: Structure, function, and regulation. Annual Review of Biochemistry, 86, 129-157. doi:10.1146/annurev-biochem-060815-014922
Zhu, Y., Zhu, R., He, Z., Liu, X., & Liu, H. (2015). Association of MTHFR C677T with total homocysteine plasma levels and susceptibility to Parkinson's disease: A meta-analysis. Neurological Sciences: Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 36(6), 945-951. doi:10.1007/s10072-014-2052-6
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Original publications
I Ylönen, S., Ylikotila, P., Siitonen, A., Finnilä, S., Autere, J., & Majamaa, K. (2013). Variations of mitochondrial DNA polymerase γ in patients with Parkinson's disease. Journal of Neurology, 260(12), 3144-3149.
II Ylönen, S., Siitonen, A., Nalls, M.A., Ylikotila, P., Autere, J., Eerola-Rautio, J., Gibbs, R., Hiltunen, M., Tienari, P.J., Soininen, H., Singleton, A.B., & Majamaa, K. (2017). Genetic risk factors in Finnish patients with Parkinson's disease. Parkinsonism and Related Disorders, 45, 39-43.
III Ylönen, S., Sipilä, J., Hietala, M. & Majamaa K. (2019) HTT haplogroups in Finnish patients with Huntington disease. Neurology Genetics, 5(3), e334.
Reprinted with permission from Springer Nature (I), Elsevier (II) and Wolters
Kluwer Health, Inc. (III).
Original publications are not included in the electronic version of the dissertation.
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