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Ageing Research Reviews 14 (2014) 1930

Contents lists available at ScienceDirect

Ageing Research Reviews

jou rn al hom epage: www.elsev ier .com/ locate /ar r

Review

Ageing and Parkinsons disease: Why is advancing age the biggestrisk factor?

Amy Reea Newcastle Unb Wellcome Tru

a r t i c l

Article history:Received 10 SeReceived in reAccepted 24 JaAvailable onlin

Keywords:Parkinsons diMitochondriaAgeingNeurodegener

of the symptoms seen in Parkinsons disease. We review the evidence that ageing is important for thedevelopment of Parkinsons disease and how age related decline leads to the loss of neurons within thisdisease, before describing exactly how advancing age may lead to substantia nigra neuronal loss andParkinsons disease in some individuals.

2014 The Authors. Published by Elsevier B.V.

Contents

1. Introd2. The en

2.1. 2.2. 2.3. 2.4.

3. Mitoc3.1.

4. Impai

CorresponTel.: +44 0191

E-mail add

1568-1637 http://dx.doi.o

Open access under CC BY license.uction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20vironment of the substantia nigra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Dopamine metabolism and oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Calcium dynamics and pacemaking activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Iron concentration and changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Neuromelanin accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

hondrial dysfunction within substantia nigra neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Respiratory deciency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223.1.1. mtDNA mutation load . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223.1.2. Disruption of key mitochondrial processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233.1.3. Interaction with alpha synuclein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243.1.4. PD symptoms in patients with mitochondrial disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

rment of protein degradation in substantia nigra neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254.1. The ubiquitin proteasome system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254.2. Autophagy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

ding author at: Wellcome Trust Centre for Mitochondrial Research, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.2228565; fax: +44 01912228553.resses: [email protected] (A. Reeve), [email protected] (E. Simcox), [email protected], [email protected] (D. Turnbull).

2014 The Authors. Published by Elsevier B.V. rg/10.1016/j.arr.2014.01.004

Open access under CC BY license.vea,b, Eve Simcoxa,b, Doug Turnbull a,b,

iversity Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, UKst Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, UK

e i n f o

ptember 2013vised form 6 January 2014nuary 2014e 3 February 2014

sease

ation

a b s t r a c t

As the second most common age related neurodegenerative disease after Alzheimers disease, the health,social and economic impact resulting from Parkinsons disease will continue to increase alongside thelongevity of the population. Ageing remains the biggest risk factor for developing idiopathic Parkinsonsdisease. Although research into the mechanisms leading to cell death in Parkinsons disease has shed lighton many aspects of the pathogenesis of this disorder, we still cannot answer the fundamental question,what specic age related factors predispose some individuals to develop this common neurodegenera-tive disease. In this review we focus specically on the neuronal population associated with the motorsymptoms of Parkinsons disease, the dopaminergic neurons of the substantia nigra, and try to under-stand how ageing puts these neurons at risk to the extent that a slight change in protein metabolismor mitochondrial function can push the cells over the edge leading to catastrophic cell death and many

20 A. Reeve et al. / Ageing Research Reviews 14 (2014) 1930

5. Comparison with other neuronal populations that are vulnerable in PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

1. Introdu

Parkinsothe age of uals (or 500the age of 8that advanc(de Lau anKaczmar etage, a smalwith sympthese casesgenes whicfunction, inand alpha-sin either isfamilial, eamal dominto sporadicbut also maogy.

Whilst Ptoms, an imand the maiorder, is thedopaminergestingly, thwith normaof over 750ically deneneuronal loLewy body SN has beeestimated t1991), whiloss of neu1999b).

Many stregions witcell loss sibers have old age wlary nucleuwhile it waa loss of oGundersen other dopamtal area an50% (Hirschgic neuronwith ageinrelated to opus.

An undemay yield imthe literatuthe SN, whywith advan

env

neud, sh

to oughctionr et terised s

degenes

opam

ougducts aretabonoaming oine i

preain press ing de reminsion aininn acc

PD c999a

lcium

ent sntia activo areet alakinaminy is m

havetioner, inls ad indipis ag

to cel sy

wayconcetratiction

ns disease (PD) affects over 1% of the population over60, which in the UK equates to over 127,000 individ-,000 individuals in the USA), while in individuals over5 this prevalence reaches 5%, highlighting the impacting age has on the risk of developing this conditiond Breteler, 2006; Nussbaum and Ellis, 2003; Wood-

al., 2006). Although thought of as a disease of oldl percentage of patients (about 5% of all cases) presenttoms before the age of 60 years and the majority of

are caused by mutations in an ever increasing list ofh affect either protein metabolism or mitochondrialcluding Pink1 (PARK6), Parkin (PARK 2), DJ-1 (PARK7)ynuclein (PARK 1), thus highlighting that dysfunction

sufcient to cause PD (Gasser et al., 2011). Theserly onset forms of Parkinsons disease can be autoso-ant or recessive and may show a similar phenotype

PD in terms of symptoms and response to L-Dopa,y present with different symptoms and neuropathol-

arkinsons disease involves a complex array of symp-portant brain region affected by severe cell loss in PD,n cause of the motor symptoms associated with this dis-

substantia nigra (SN). Specically within the SN it is theic neurons of the pars compacta that are lost and inter-is brain region also shows more pathological changesl ageing than any other region (Fig. 1). A recent study

elderly individuals (mean age 88.5 years) without clin-d PD, has shown that nearly 1/3 showed mild to severess within the substantia nigra, with 10% also showingpathology (Buchman et al., 2012). Cell loss within then shown to be extensive (Rudow et al., 2008) and waso occur at a rate of 4.7% per decade (Fearnley and Lees,le more recent stereological techniques estimate thisrons to occur at a rate of 9.8% per decade (Ma et al.,

udies have measured neuronal loss in other brainh ageing, although none have shown any degree ofmilar to that seen within the SN. Neuronal num-been shown to remain relatively stable throughoutithin the hippocampus, putamen, medial mammil-s, hypothalamus and the nucleus basalis of Meynert,s estimated that the neocortical neurons might shownly 10% over the entire lifespan (Pakkenberg and(1997) and reviewed in Lowe (2008)). However, ininergic populations including in the ventral tegmen-

d the retrorubral area, cell loss might actually reach et al., 1987). These studies show that dopaminer-

al populations seem preferentially vulnerable to lossg compared to many other brain regions and thosether neurodegenerative disorders e.g. the hippocam-

rstanding of why these SN cells die with advancing ageportant insight into why cells are lost in PD. We review

re to dene how increasing age affects the neurons of

2. The

Thementerelatedalso thdysfun(Bendecharacincreasproteinpathog

2.1. D

Alththe proneuronthe meby moincluddopaming theThe mtive stdamagthen bmonoaexpresDAT stthis caloss inet al., 1

2.2. Ca

Recsubstaring but als(Chan pacemof dopactivitwhichpopulaHowevchanneinduceby Israneuronknownin mod

Thecium seques these cells in particular are lost and show dysfunctioncing age, particularly in PD.

Mitochondneurons to ironment of the substantia nigra

rons of the SN are distinct in many ways. They are pig-ow pacemaking activity and increased oxidative stressthe metabolism of dopamine within them. They aret to be particularly susceptible to the mitochondrial

which accumulates within them with advancing ageal., 2006; Kraytsberg et al., 2006). Here we consider thetics of SN neurons which may predispose them to anensitivity to mitochondrial dysfunction and changes inradation pathways, which may in turn be key to theis of Parkinsons disease.

ine metabolism and oxidative stress

h a signicant amount of oxidative stress is generated byion of reactive oxygen species within mitochondria, SN

believed to be under additional oxidative stress due tolism of dopamine within them. Dopamine metabolismine oxidase generates a number of oxidative speciesxygen radicals and H2O2, while the oxidation oftself might occur through a number of processes includ-sence of transition metals (reviewed in (Sulzer, 2007)).rotector of dopaminergic neurons against this oxida-is the dopamine transporter (DAT). DAT takes theopamine back into the nerve terminal where it can

packaged into synaptic vesicles by VMAT2 (vesiculare transporter 2). There have been reports that DATdeclines with age in the dorsal tier of the SN but thatg is greatest in the ventral tier, suggesting that perhapsount for some of the susceptibility of these neurons toompared to the population within the dorsal tier (Ma).

dynamics and pacemaking activity

tudies have implicated that the calcium handling ofnigra neurons and the importance of calcium for theirity are key to the pathogenesis of Parkinsons disease

an avenue through which to achieve neuroprotection., 2007). The neurons of the SN exhibit autonomousg activity, believed to be important for the maintenancee levels within the striatum. In adult neurons thisaintained by specic calcium channels (CaV1.3L-type)

recently been shown to be prevalent in other neuronals which are vulnerable in PD (Goldberg et al., 2012).

juvenile neurons this activity is maintained by sodiumnd a reversion to juvenile forms of activity can be

adult neurons by blockage of the calcium channelsne. Interestingly, this reversion also protects the SNainst treatment with the mitochondrial toxin rotenone,ause specic SN neuronal loss and PD-like symptomsstems (Chan et al., 2007).

in which these neurons handle calcium and the cal-ntration within them is hugely important and itson within mitochondria is key for cellular survival.

ria are responsible for the modulation of calcium withinmaintain intracellular levels, particularly important for

A. Reeve et al. / Ageing Research Reviews 14 (2014) 1930 21

Fig. 1. Change ls shoproteins inclu nd nesurvival image tion opotential and cing respectively. T tion in

the mainterons differethat neuronresponses tof intracellulevels withto accumulextrusion owithin the npermeabilitdrial bioeneby oxidativnumber of r

2.3. Iron co

The ironan importaticularly bathe Fenton niques to abrain nuclean increasethat a signiSN pars comDexter et althis data reno change icontrols (rethat the ironing to a potesince neuroit, again giv

euro binduromins (Ds within SN neurons with advancing age. (A) There is an increase in the number of celding complex I subunits (arrow). Changes in mitochondrial membrane potential a

B, shows the mitochondrial network of a healthy neuron within culture, fragmentaprior to degradation through mitophagy. There is a loss of SN neurons with advanhe loss of neurons can be seen as a loss of pigmented cells even at a low magnica

nance of neuronal excitability. In fact, studies in neu-ntiated from transmitochondrial cybrids have showns showing mitochondrial dysfunction show altered

o multiple stimuli which leads to a prolonged elevation

these nfor ironthat nemelanlar calcium (Trevelyan et al., 2010). Changes in the ATPin neurons such as those that may occur in responseating mitochondrial DNA mutations would affect thef calcium. This may lead to an overload of calciumeurons which in turn would lead to the mitochondrialy transition which then causes a loss of mitochon-rgetic function. These events might also be initiated

e stress which as discussed previously may occur for aeasons with advancing age within the neurons of the SN.

ncentration and changes

content of substantia nigra neurons is thought to bent contributor to their susceptibility to loss in PD, par-sed on the generation of reactive oxygen species byreaction. Several studies, using various imaging tech-ssess how the iron content of the SN and other deepi changes with advancing age, have shown that there is

in the iron content of the SN with advancing age andcant increase occurs above the age of 40 within thepacta (Bilgic et al., 2012; Daugherty and Raz, 2013;

., 1989; Haacke et al., 2010; Soc et al., 1991). Howevermains inconclusive since other studies have reportedn the iron content of these neurons in PD compared toviewed in Friedman et al. (2007)). This does not mean

content of these neurons is not important. It links age-ntially detrimental characteristic of these neurons, andmelanin (see below) is believed to bind iron and chelatees a plausible link between two important features of

dria, in parincluding coTherefore cthese neuroand could tleading to a

2.4. Neurom

The pigmlation of newith advanmolecules aoxidative styear of lifeet al., 2006but also proexplaining echolamine(2008)). Neergic populventral teget al. (2008viduals witfor cell surneurons. Neenger, a regcations. Thewing mitochondrial dysfunction, including a loss of key mitochondrialtwork dyanmics have also been shown to be important for neuronalf this network is associated with changes in mitochondrial membraneage, images C and D show the SN of a 69 year old and a 53 year old

the SN of the 69 year old.

ns. The afnity of iron for melanin is much lower thaning proteins such as ferritin, however it has been shownelanin does have a higher afnity for iron than otherouble et al., 2003; Shima et al., 1997). The mitochon-

ticular a number of electron transport chain proteins,mplex I, rely on iron sulphur clusters for their function.

hanges in the concentration or availability of iron withinns will additionally impact on mitochondrial functionhus exacerbate any mitochondrial dysfunction further,

loss of these neurons.

elanin accumulation

entation of substantia nigra is due to the accumu-uromelanin within them. This pigment accumulatescing age, is composed of many different proteins andnd may afford SN neurons with some protection againstress. Neuromelanin begins accumulating from the 3rd

and shows a progressive increase with age (Fedorow; Halliday et al., 2005). It is composed of mainly lipidsteins and products from the metabolism of dopamine,its distribution within very select populations of cat-

neurons within the brain (reviewed in Double et al.uromelanin is also found within other catecholamin-ations, including the neurons of the locus coeruleus,mental area and hypothalamus (reviewed in Double)). Although this pigment accumulates within all indi-h advancing age it has been implicated to be importantvival and in PD, for the vulnerability of dopaminergicuromelanin has been proposed to be a free radical scav-ulator of intracellular iron and an inactivator of cellularrefore it is not surprising that changes in neuromelanin

22 A. Reeve et al. / Ageing Research Reviews 14 (2014) 1930

have been implicated to be important, contributing to the selectivevulnerability of dopaminergic neurons in PD.

It has been shown that the ventral tier of the SN, which shows themost profound cell loss in PD, contains less neuromelanin than thesomewhat mmight have1991). Otherons of the brain of heaprotect thes1992; Zecca

3. Mitochoneurons

The effevival of neuand althougand the lossis yet to be

Mitochofor the pathMPP+ causeof complexLangston anof decreasefrom patienof the SN arwithin the and specicbeen increasupport howaffect cellullikely to beimpact on n

3.1. Respira

The speccomplex I hsince its inhSN neuronsLangston etdecline in ttissue usingimately 3% compared treported up2006; Itoh eet al. prediolds wouldbegin fromrespiratoryto comprommodelling dtial within complexityproductionwould furth2013).

3.1.1. mtDNThe resp

been showntions and thet al., 2006;

in other brain regions and tissues where respiratory deciency isbelow 15% with even advanced age and unlike some other agedtissues there is no accumulation of mtDNA point mutations withinthe SN (Reeve et al., 2009; Taylor et al., 2003). Several studies have

red te SN igheronta2011

del. Thf thee butoweorralncy dneurond m

The how

of p (Lax

uronysfun

is liken inougnismd thochoform

to thmag

but . Thiho so theressi

stra andoms e fory to hen lally cusly b

coullar arupti

phen2007

prooThe

ing ke in nd dportumuage ry thtochinerpor

inerEkstaminore preserved dorsal tier, suggesting that this pigment a protective effect within these neurons (Gibb and Lees,r studies have also suggested that the pigmented neu-SN contain less neuromelanin in PD brains than in thelthy controls, again suggesting that this pigment mighte neurons against intracellular stressors (Kastner et al.,

et al., 2001).

ndrial dysfunction within substantia nigra

ct of mitochondrial dysfunction on the health and sur-rons within the SN has been debated for over 3 decades,h undoubtedly a contributor to the pathogenesis of PD

of these neurons, the exact role that this organelle playselucidated.ndrial dysfunction has been implicated to be importantogenesis of Parkinsons disease since the discovery thats rapid parkinsonism and SN cell loss through inhibition

I of the electron transport chain (Langston et al., 1983;d Ballard, 1983). This discovery was followed by reportsd complex I activity and protein expression in tissuests with PD (Schapira et al., 1989, 1990). The neuronse thought to be particularly susceptible to dysfunctionmitochondria and support for a role for mitochondria,ally their dysfunction in the loss of SN neurons in PD, hassing over recent years. This section reviews the data to

an age related decline in mitochondrial function willar function and survival. Mitochondrial dysfunction is

a key player in the loss of these neurons based on itseuronal processes and function (reviewed in Fig. 2).

tory deciency

ic inhibition of key mitochondrial proteins includingas been known to cause Parkinsonian like symptomsibitors, MPP+ and rotenone, were shown to cause loss of

in both man and model systems (Betarbet et al., 2000; al., 1983). Respiratory deciency can be dened as ahe activity of complex IV which can be visualised in

the COX/SDH assay. Bender et al. report that approx-of SN neurons are COX decient in patients with PDo 1% in age matched controls, while other studies have

to 30% COX deciency in some cases (Bender et al.,t al., 1996; Kraytsberg et al., 2006). Furthermore, Elsoncted that 14% of post mitotic cells in 80120 year

be COX decient and that this accumulation would the age of 60 (Elson et al., 2001). The development of

deciency within the neurons of the SN, may also leadised production of ATP. Therefore considering recentata suggesting that the propagation of the action poten-SN neurons is highly energy dependent based on the

of the axonal arbour of these neurons, a decrease in the of ATP will affect the excitability of these neurons whicher increase their vulnerability (Pissadaki and Bolam,

A mutation loadiratory (COX) deciency detected within the SN has

to be caused specically by mitochondrial DNA dele-ese deletions were found to reach levels of 50% (Bender

Kraytsberg et al., 2006). This deletion load is higher than

compaand thto be harea, fret al., mtDNAing agelevel oing agSN folllum (Cdecieother (AD) a2012).been sbellumdiseasethe nedrial dthen itloss se

Althmechathesiseto mitto the leadingThis daabove,the SNet al. wPst1, tof expdoublemationsymptfore this likelThey teventupreviowhichparticu

Disageinget al., with aPOLG. includincreastions athe imthe accof the study bthe midopamand imdopamsions (in dophe mtDNA deletion load between other brain regionsin both ageing and PD. Deletion levels have been found

in the SN than in the locus coeruleus, ventral tegmentall cortex and the putamen (Bender et al., 2008; Elstner). While in 1992 two studies investigated the level ofetions within 12 different brain regions with advanc-ey found that in many of the brain regions studied the

common mtDNA deletion accumulated with advanc- that the levels of this mutation were highest in thed by the basal ganglia, cortical areas and the cerebel--Debrinski et al., 1992; Soong et al., 1992). Respiratoryue to high mtDNA deletion levels is however found innal populations in patients with Alzheimers diseaseultiple sclerosis (Campbell et al., 2011; Krishnan et al.,level of mtDNA mutation and respiratory deciency hasn to correlate with the cell loss seen within the cere-atients affected by ataxia as part of their mitochondrial

et al., 2012). This data therefore would suggest that ifs of the SN are particularly susceptible to the mitochon-ction shown to cause cell loss elsewhere in the brain,ely that this dysfunction is also associated with the cell

PD.h there is no denitive evidence as yet to support a

for the formation of these deletions, we have hypo-at they could be formed through the repair of damagendrial DNA (Krishnan et al., 2008). This damage leadsation of double strand breaks which are then repairede loss of several kilobases of the mitochondrial genome.e could be due to a number of the processes describedis likely to reect the highly oxidative environment ofs theory has been strengthened by the work of Pickrellpecically targeted a mitochondrial restriction enzyme,

neurons of the SN. They showed that the inductionon of this enzyme led specically to the formation ofnd breaks within the mtDNA leading to deletion for-

depletion, and importantly the development of motorand SN neurodegeneration (Pickrell et al., 2011). There-mation of these mutations within human SN neuronsbe a consequence of the processes mentioned above.ead to reduced mitochondrial function, ATP levels andell death. In addition mitochondrial DNA deletions haveeen shown to cause a reduction in proteasomal activity

d exacerbate the accumulation of misfolded protein, inlpha-synuclein, as discussed below (Alemi et al., 2007).on of mitochondrial DNA integrity in mice causes anotype and the loss of dopaminergic neurons (Ekstrand; Trifunovic et al., 2004). Initially, mice were createdf reading decient knock-in of the mtDNA polymerase,se mice developed a premature ageing phenotypeyphosis, weight loss and osteoporosis, caused by ansomatic mtDNA mutations, including both point muta-eletions (Trifunovic et al., 2004). This study highlightedance of mitochondrial DNA for ageing and hinted thatlation of defects within this genome could lead to manyelated changes that occur. Furthermore, a subsequente same group showed that the conditional knock-out ofondrial transcription factor A, Tfam, specically withingic neurons causes a reduction in mtDNA expressiontantly progressive parkinsonism within the mice,gic neuron loss and the accumulation of protein inclu-rand et al., 2007). The expression of mutated Twinkleergic neurons has shown the importance of mtDNA

A. Reeve et al. / Ageing Research Reviews 14 (2014) 1930 23

Fig. 2. Mitoch Parkimitochondrial een) cDNA deletions ts keyof PD. Mitocho s and hoxidative stres complinhibition of co TP (blwith ER has b ssociamitochondria orms affect their fun tosomfunction as we ndicattarget the mito the SN

deletions ichanges in mitochondrolder mutacorrelated wdevelopmemtDNA delein the expreteasomal acdisruptionsto cause thethus the imfunction widisease.

3.1.2. DisruAs the n

PD increasedrial dynamwithin the SDJ-1 in drosin mitochon2006; Gree2011; Park been shownand changedria sugges2011). Muta loss of mthe electronmitochondrondrial dysfunction has been implicated to be important for the pathogenesis of biology have been linked to PD. This gure shows how a healthy mitochondrion (gr

(shown as smaller mtDNA molecules), and becomes dysfunctional (red) and highlighndrial DNA deletions lead to mitochondrial dysfunction and respiratory deciencies. Changes in the expression and activity of mitochondrial electron transport chain mplex I causes PD like symptoms in model systems treated with toxins such as MP

een shown to be important for mitochondrial calcium handling (green) and this ais important for the maintenance of cellular homeostasis. Alpha-synuclein, which fction. Finally proteins encoded by a number of genes known to be mutated in aull as the targeting of mitochondria to mitophagy. Once phosphorylated by Pink1 (ichondria for degradation. These processes will all affect the survival of neurons inn the survival of SN neurons and also highlightedthe expression of parkin, an important protein in theial degradation pathway. Song et al. showed that innt mice there was a specic loss of SN neurons whichith the development of motor defects, and that the

nt of the SN cell loss was related to the accumulation oftions. Interestingly, mutant Twinkle causes a reductionssion of parkin within the midbrain and decreased pro-tivity (Song et al., 2012). This evidence highlights that

of mtDNA within dopaminergic neurons are sufcient symptoms and neuropathology associate with PD andportance of the accumulation of mitochondrial dys-th advancing age to the probable pathogenesis of this

ption of key mitochondrial processesumber of genes in which mutations are associated withs so too does the evidence that changes in mitochon-ics and turnover are important for the loss of neuronsN. The knockout of alpha-synuclein, pink1, parkin andophila and cell culture based models leads to alterationsdrial morphology and network formation (Clark et al.,ne et al., 2003; Martin et al., 2006; Nakamura et al.,et al., 2005, 2009). Mutations in alpha-synuclein have

to cause fragmentation of the mitochondrial networks in the ultrastructure and distribution of the mitochon-ting increased mitochondrial ssion, (Nakamura et al.,ations in Pink1 and Parkin have been shown to causeitochondrial ultrastructure as observed as changes in

density of the mitochondria and fragmentation of theial network (Clark et al., 2006; Greene et al., 2003). A

loss of DJ-1increased met al., 2012when LRRK2013; Mort

A recenttein importof striatal pno effect ona dramatic nals in the in striatal d2012). Mfn the mitochis reliant o(ER) and ththe mitochat the contaScorrano, 2DJ-1 and paof the mitoeffects of pogy (Ottolinbeen showthe mitochdria with thcalcium upSN, as mening activitymaintain cathe activitynsons disease for nearly 30 years. A number of different aspects ofhanges with advancing age, for example accumulating mitochondrial

proteins and processes that have been implicated in the pathogenesisave been linked to the generation of ROS (yellow) and the associatedexes I and IV have been found in the elderly and patients with PD andue/green) and rotenone (purple). The association of the mitochondriation relies on mitofusin 2 and DJ-1. The buffering of calcium by theLewy bodies, has also been shown to interact with mitochondria andal recessive forms of PD have functions important for mitochondrialed by P), Parkin ubiquinates a number of mitochondrial proteins to

with advancing age. causes a loss of mitochondrial membrane potential anditochondrial fragmentation (Thomas et al., 2010; Wang) and mitochondrial changes have also been reported2 (Leucine rich repeat kinase 2) is mutated (Goo et al.,iboys et al., 2010).

paper has also shown that mitofusin2 (mfn2), a pro-ant for mitochondrial fusion, is essential for the survivalrojections from the SN. Indeed knockout of mfn2 has

the number of dopaminergic SN neurons but causesreduction in the number of dopaminergic nerve termi-striatum of affected mice, an accompanying reductionopamine levels and locomotor disturbances (Lee et al.,2 is also a key protein for the handling of calcium withinondria, the ability of mitochondria to take up calciumn their close proximity to the endoplasmic reticulumerefore the site of calcium release. The proximity ofondria to the ER is reliant on mfn2 which is enrichedct sites between the ER and mitochondria (de Brito and008). Recent evidence has also linked the expression ofrkin to this interaction, DJ-1 modulates the interactionchondria and the ER and in doing show suppresses the53 on mitochondrial calcium handling and morphol-i et al., 2013). Interestingly, parkin overexpression has

n to also enhance the calcium handling capabilities ofondria by enhancing the interaction of the mitochon-e ER without a subsequent effect on the mitochondrialtake machinery (Cali et al., 2012). The neurons of thetioned above, use calcium to maintain their pacemak-

and therefore changes in how the neurons handle andlcium levels are going to be hugely inuential on both

and survival of these neurons.

24 A. Reeve et al. / Ageing Research Reviews 14 (2014) 1930

Both ssion/fusion and mitochondrial movement require intactmitochondrial membrane potential (m) and a loss of thispotential is associated with mitochondrial degradation throughmitophagy (Twig et al., 2008). Subtle differences in m havealso been mitochondrbrane potenSheetz, 200(Verburg ancybrids having a severincreased mutations iet al., 2010)is interestintion and exaged SN neuthe degradapathway, mfollowed byOPA1 expretransport hneurodegenHuntington2012). In Pport occur ishown to insible for thproteins (Amitochondrdo not losewould persiaccumulateover time.

Parkin athe targetinbelow). Thepersist withcause a losssion wouldrelated decpink1 and of mitochonThese intersubunits oferentially tproteins, radria. Furthemitochondrprotein deg

3.1.3. InteraThe path

including dmain protealthough boand the toxit seems likmost toxic (a widely exet al., 2013)cle recyclinmechanismbe requiredHowever, w-sheet con

This pattern is interestingly also observed for brillar deposits inother neurodegenerative disorders including Alzheimers disease,and aggregated alpha-synuclein is strikingly similar to amyloid(Bendor et al., 2013; Chiti and Dobson, 2006). Alpha synuclein has

en foy prenz ealso oms

a payramny mregaantlyosph

2012mtDNe anhich

protatho

mitoex I, nce ithin

protne anr theationies o

agermaat thoogy aodieon pulatiha-syonddant ein wrmen008y to ng SNhowffectiighlihanga et synuN doand clus006)ith m006)N pale LBn et ise wally te facttudievelopf incattributed to determining directionality of neuronalia, for example 80% of mitochondria with a low mem-tial are transported towards the cell body (Miller and4), although this might not be such a clear cut distinctiond Hollenbeck, 2008). Studies using transmitochondriale shown that neurons with mtDNA mutations caus-e mitochondrial complex I defect have a signicantly

m, due to reversal of the ATP synthase, howevern complex IV seemed to not affect the m (Abramov. The effect of these mutations on the m in these cellsg considering the effect on mitochondrial protein func-pression of the accumulating mtDNA defects we see inrons. It has been proposed by a number of studies thattion of mitochondria through the specic autophagyitophagy, is heavily reliant on the dissipation of m,

ssion from the mitochondrial network and loss ofssion (Twig et al., 2008). Alterations in mitochondrialave been implicated to be important in a number oferative conditions including Alzheimers disease ands disease (Reddy and Shirendeb, 2012; Reddy et al.,arkinsons disease, alterations in mitochondrial trans-n response to rotenone treatment and pink1 has beenteract with Milton and Miro, two key proteins respon-e interaction of mitochondria with neuronal motorrnold et al., 2011; Weihofen et al., 2009). Therefore ifia which harbour defects of the electron transport chain

their m then they will not leave the network andst within the neuron, which might explain why neurons

such a high proportion of dysfunctional mitochondria

nd pink1 have been implicated to be important forg of mitochondria for degradation (discussed in detailrefore the very fact that dysfunctional mitochondriain a neuron and accumulate to a level sufcient to

of complex IV activity and complex I protein expres- suggest that this pathway in particular shows an ageline. Recent evidence suggests that the interaction ofparkin might actually facilitate the specic turnoverdrial respiratory chain subunits (Vincow et al., 2013).actions might suggest a reason for the loss of key

the electron transport chain, as the system might pref-arget these subunits, reducing the expression of thesether than degrading intact, yet dysfunctional mitochon-rmore this might lead to the accumulation of misfoldedial proteins which would put further burden onto theradation pathways, described below.

ction with alpha synucleinological hallmark of PD and other synucleinopathies

ementia with Lewy bodies (DLB), is the Lewy body. Thein component of these structures is alpha synuclein,th the effect of these inclusions on neuronal survivalicity of different forms of this protein are still debated,ely that the oligomeric forms of alpha-synuclein are thereviewed in Kalia et al. (2013)). Alpha-synuclein itself ispressed protein, with an alpha helical structure (Bendor, and is believed to be important for the synaptic vesi-g (Cheng et al., 2011; Murphy et al., 2000). The exact

that leads to the conformational change believed to for its aggregation in PD needs to be fully elucidated.hat is clear is that Lewy bodies and neurites show a hightent and a distinctive cross- X-ray diffraction pattern.

also beestingl(Leverogy is symptogy inextrap

Mathe aggimportand phet al., lating to havrons, wof thisbody pof keycompland hetein wof thisrotenomonitoinformsubtletwithinthat noand thpatholLewy bmulatiaccum

AlpmitochdepensynuclI impaiet al., 2is likelin ageibeen slarly ahave hronal c(Botellalpha show Stypes with inet al., 2ated wet al., 2show Sexamp(Martithat arespeciand ththese sthe dethose ound to aggregate in many cases of AD although inter-edominantly within the amygdala rather than the SNt al., 2008; Uchikado et al., 2006). Lewy body pathol-seen in elderly individuals with no Parkinsons diseaseand recently we found evidence of Lewy body pathol-tient with POLG mutations, but with no correspondingidal features (Reeve et al., 2013).odications have been proposed to be important fortion of alpha-synuclein and its conformational change,

these include oxidation, the presence of heavy metalsorylation (reviewed in Bendor et al. (2013)) (Breydo; Fujiwara et al., 2002; Giasson et al., 2000). Accumu-A mutations or dysfunctional mitochondria are likely

effect on the oxidative stress levels within SN neu- might contribute to the misfolding and accumulationein. However, in a recent study we showed that Lewylogy was associated with neurons with intact expressionchondrial electron transport chain proteins, includingsuggesting at least that intact mitochondrial functionATP levels are required for the aggregation of this pro-

the cell body, perhaps relating to the transportationein (Reeve et al., 2012). Numerous studies have usedd other toxins to induce mitochondrial dysfunction and

accumulation of alpha-synuclein, despite the wealth of that these studies provide they often do not reect thef the slow accumulation of mitochondrial dysfunctioning substantia nigra neurons. Our data might suggestl mitochondrial function might protect against cell lossse cells with mitochondrial dysfunction and Lewy bodyre lost, or that the accumulation of alpha-synuclein intos requires mitochondrial function and that this accu-revents toxic, damaging alpha-synuclein species fromng at synapses.nuclein itself has been shown to interact with

ria and be imported into the mitochondria in an energymanner (Devi et al., 2008). The accumulation of alpha-ithin mitochondria has been shown to lead to complext, decreased m and increased ROS production (Devi

; Parihar et al., 2008, 2009). The effect of these changesbe an exacerbation of the mitochondrial defect present

neurons. Mutations in the alpha-synuclein gene haven to cause changes in mitochondrial structure particu-ng the cristae in cell culture, while drosophila modelsghted the contribution of oxidative stress to the neu-es, for example showing hypersensitivity to hyperoxiaal., 2008). Transgenic mice expressing mutant forms ofclein have also been generated but they often do notpaminergic neuronal loss, despite very severe pheno-neuron loss in other brain regions closely associatedion formation and mitochondrial degeneration (Martin. Interestingly, this neurodegeneration was also associ-tDNA damage and a loss of complex IV activity (Martin. It is worth noting that although such models may notthology they often show pathology in other regions, for-like inclusions in the motor neurons of the spinal cordal., 2006). However, there are a number of difcultieshen trying to model human disease in mice and this isrue for the SN, when you consider the life span of mice

that their SN neurons do not contain neuromelanin. Buts do highlight the close relationship and importance forment of neuronal loss of two age related phenomena,reased mtDNA damage and also protein accumulation.

A. Reeve et al. / Ageing Research Reviews 14 (2014) 1930 25

3.1.4. PD symptoms in patients with mitochondrial diseaseIf mitochondrial dysfunction is particularly important in the

pathogenesis of PD then we might expect to see PD symptomsin patients with mitochondrial disorders and potentially at ayounger agthat changthis brain rdefects tha(Reeve et amouse haveSN neuronachanges incdria and coAlthough ewith mitochof Parkinsocases thereLewy body 2004) and a POLG patoms (ReevPOLG patienof sporadicbut some cHudson et lier onset cwhether cofore it is dicausative othese sympfor other mseen in thethe parkinsexhibit thiscell loss wilike symptotions withinassociationsions within2010; Balafshown a trand PD in Sweden (An2010). Thedetrimentalation of mage. Althouassociated there are retoms (Casa2001; Simo

In addititain mtDNAdevelopmeJ, K are protwithin Eurogested thatet al., 20132005; van dhaplogroupPD (Mehta ePD with adlogroup HVsubtle chanhood of devof this disea

4. Impairment of protein degradation in substantia nigraneurons

There are two main pathways within neurons for the degrada-d re

(UPh wghtecien011

ATPpmeions to afposedses.

accu is r

troge the

predwithroteieaseaccumuld u.

e ub

ubiqr pro

to ubwheoteasd. Pros, reqsomets. Bectionion os thetin p

tision ito agner,y onng os ha

the pwy bc ablsymein cc capteasEmm

toph

croaus occ

the s reqle me than in the case of sporadic PD. We have shownes within the SN, and in particular cell loss withinegion, is more closely associated with mitochondrialt are acquired rather than those that are inheritedl., 2013). While a recent study in the POLG D257A

shown that mtDNA deletions were not associated withl degeneration and actually induced neuroprotectiveluding changes in the ultrastructure of the mitochon-mpensatory changes in m (Perier et al., 2013).xtrapyramidal features are relatively rare in patientsondrial disorders there have been a number of reportsnism associated with mutations within POLG. In these

is often pigmented SN neuron loss and on occasionspathology (Betts-Henderson et al., 2009; Luoma et al.,however we have detected Lewy body pathology intient with no discernible cell loss or PD-like symp-e et al., 2013). The age of onset of PD symptoms ints seems to vary with many being within the range

PD (Betts-Henderson et al., 2009; Luoma et al., 2004),ases show an earlier onset (Davidzon et al., 2006;al., 2007; Mancuso et al., 2004). Many of these ear-ases have a family history, but they do not reportmmon PD genes were screened for mutations, there-fcult to fully dissect whether the POLG mutation isf the PD-like symptoms. However, the incidence oftoms in patients with POLG mutations is higher thanitochondrial patients and abnormal DAT scans are oftense patients. If the POLG mutation was responsible foronism then one might expect most POLG patients to

phenotype, many patients with POLG mutations havethin the SN, but this is not always associated with PDms (Reeve et al., 2013). Aside from pathogenic muta-

the POLG gene, several studies have investigated the with PD of changes within the poly-glutamine expan-

the POLG1 gene in different populations (Anvret et al.,kan et al., 2012; Eerola et al., 2010). These studies haveend towards an association with non10-11Q repeatspopulations from Norway, America (Caucasian) andvret et al., 2010; Balafkan et al., 2012; Eerola et al.,

se cases highlight that mitochondrial dysfunction isl for the survival of SN neurons and that the accumu-tDNA mutations affects their survival with advancinggh mutations in POLG are the most common to bewith parkinsonism in mitochondrial disease patients,ports of point mutations associated with these symp-li et al., 2001; Horvath et al., 2007; Siciliano et al.,n et al., 1999).on, several studies have also investigated whether cer-

haplogroups are associated with susceptibility for thent of PD. Many studies seem to agree that haplogroupsective against the development of Parkinsons diseasepean populations, while a large study has also sug-

T and super-haplogroup JT are also protective (Hudson; Huerta et al., 2005; Latsoudis et al., 2008; Pyle et al.,er Walt et al., 2003). However in other populations theses are not associated with a decreased risk of developingt al., 2009). Furthermore an increased risk of developingvancing age has been associated with the superhap-

(Hudson et al., 2013). These data highlight that evenges within the mitochondria may impact on the likeli-eloping PD and thus be important for the pathogenesisse.

tion ansystemthroug(highliand efet al., 2requiredeveloreductlikely predisproces

Theing ageand niwithinthe SNstress cient pan incrto the and coregion

4.1. Th

Thecellulalinkedsome, 26S prthe enprocesproteaponendysfuninhibitgationubiquimortemreductpared and Jenan earltargetiproteintion ofand Legenetimotor synuclteolytithe pro2005;

4.2. Au

Maprocesble forprocesa doubmoval of damaged proteins, the ubiquitin proteasomeS) and autophagy, which encompasses the routeshich substrates are degraded through the lysosomed in Fig. 3). Both systems show a reduction in functioncy with age (Jana, 2012; Li and Li, 2011; Rubinsztein), are both linked to mitochondrial function since both

and alterations in both have also been implicated in thent of both idiopathic and familial forms of PD. Althoughin the efciency of these pathways with ageing arefect many populations, the SN neurons could still be

to being more severely affected by changes in these

mulation of damaged proteins in neurons with advanc-elated to oxidative adducts caused by reactive oxygenn species which, as mentioned previously, accumulateSN with advancing age. Therefore the environment ofisposes the neurons to be under signicant oxidative

a high concentration of damaged proteins, thus ef-n degradation pathways need to be in place to cope withd demand. Failure of such pathways could contributeulation of damaging proteins such as alpha-synuclein

ltimately contribute to neuronal loss within this brain

iquitin proteasome system

uitin proteasome pathway acts to remove soluble intra-teins. Briey, the proteins to be degraded are covalentlyiquitin chains, which target the protein to the protea-

re it is unfolded and passes through the barrel of theome and the products of degradation are expelled atteolysis through the UPS is a highly energy dependentuiring ATP at all stages from ubiquitination, through

assembly, and nal degradation and recycling of com-cause of this, the system is vulnerable to mitochondrial, through reduction of energy provision and the directf the proteasome through oxidised proteins and aggre-reof. In ageing there is a qualitative reduction of theroteasome system (Emmanouilidou et al., 2010). In postsue, enzymatic reactions have shown that there is an proteasome activity in the SN of PD patients com-e matched controls (McNaught et al., 2003; McNaught

2001). Moreover, mutations in Parkin known to causeset, autosomal recessive form of PD is important for thef proteins to the proteasome and expression of parkins been shown to be reduced in PD. Furthermore, inhibi-roteasome has been shown to cause neurodegenerationody like inclusions in a number of model systems whileation of subunits of the proteasome leads to extensiveptoms (Bedford et al., 2008). Conversely, mutant alphaan cause a direct inhibitory effect on the 20S cores pro-abilities and the downregulation of several subunits ofome in the substantia nigra of PD patients (Chen et al.,anouilidou et al., 2010; Tanaka et al., 2001).

agy

tophagy (hereafter autophagy) is a highly conservedurring in most organisms from yeast to man, responsi-degradation of long lived proteins and organelles. Thisuires the sequestration of the target protein withinembrane, the autophagosome, the delivery of the

26 A. Reeve et al. / Ageing Research Reviews 14 (2014) 1930

Fig. 3. The de ays ihave been imp theseinterconnectiv efcieheat shock 70

autophagosefcient deregulator odynamic prand a numthe accumuof key autocause neurocells of the

The degspecic authave been Parkinsonsof mitochorecruitmendria requireaccumulatireecting t(Anglade ethe autophan over prothe accumuaccumulatia decrease iet al., 2012through aushould degassociated dysfunctionthat in fact clearance oproposed sally degradunfolding fmay requir

er, ish ints) tz-Er

arly deein. ationgradation of proteins and organelles through the proteasome and autophagy pathwlicated to be affected/dysregulated in Parkinsons disease. This gure reviews howity between the two protein degradation pathways means that a decrease in the kDa protein, DUB deubiquitinating enzyme.

ome to the lysosome, fusion with the lysosome and thegradation by lysosomal hydrolases. Although the mainf autophagy is the supply of nutrients to the cell, thisocess has been implicated to be important in ageingber of age related diseases, especially those involvinglation of protein aggregates within neurons. Knock-outphagy related genes, ATG 5 and 7, has been shown todegeneration in mice, particularly a loss of the Purkinje

howevthrougprotein(Alvare

Cleproteinsynucldegradcerebellum (Hara et al., 2006; Komatsu et al., 2006).radation of whole mitochondria occurs through theophagy pathway, mitophagy. A number of genes thatshown to cause familial autosomal-recessive forms of

disease are known to be important for the targetingndria to this pathway, such as Parkin and Pink1. Thet of parkin, a ubiquitin E3 ligase, to damaged mitochon-s the function of the putative kinase, Pink1. In addition,on of autophagosomes has been found in PD brainshe decrease in successful clearance in this diseaset al., 1997). This observation suggests that perhapsagy pathway becomes overwhelmed, or that there isduction of autophagosomes, perhaps in response tolating dysfunctional mitochondria. Alternatively, an

on of these end stage vesicles may actually representn autophagy and autophagic ux (Ma et al., 2012; Zhou). The pathway by which mitochondria are degradedtophagy is a tightly regulated process, which in theoryrade dysfunctional mitochondria preventing their ageaccumulation. Recent mouse studies have shown thatal mitochondria do not necessarily recruit parkin andthe absence of parkin may not affect the phenotype orf mitochondria (Sterky et al., 2011). One of the otherubstrates for Parkin is alpha-synuclein. Although usu-ed through the proteasome, alpha-synuclein requiresor degradation and aggregating forms of this proteine clearance through other pathways. Alpha-synuclein,

chaperone can bind through intand other sering that taccumulatiical that thdamaging fSimilarly, tdysfunctionciency of mmtDNA incinto changeDUBs act adation of pTheir accumthat one castructures m

5. Comparvulnerable

The neuin PD (Braaother neurrons of the other brains tightly regulated and heavily ATP dependant. Both these processes pathways are affected and the mechanism for their dysfunction. Thency of one will strongly impact on the burden of the other. HSC70

also a target for chaperone mediated autophagy, whicheractions with LAMP-2A and HSC (heat shock 70 kDaargets the alpha-synuclein directly to the lysosomeviti et al., 2010, 2013; Vogiatzi et al., 2008).one of the most relevant relationships is that of thegradation pathways and their degradation of alpha-This protein has been shown to be ubiquitinated for

through the proteasome, as well as degraded through

mediated autophagy. Mutated forms of alpha-synucleinto the lysosomal membrane without translocationeractions with Lamp-2A, essentially blocking their own,ubstrates degradation through this pathway. Consid-he pathological hallmark of Parkinsons disease is theon of Lewy body structures, it would seem only log-e systems within the cell designed to remove theseorms of alpha-synuclein might show reduced efciency.he observation that neurons within the SN accumulateal mitochondria would imply that with ageing the ef-itophagy declines as damage to the mitochondria andreases. Alongside these observations are investigationss in the expression of deubiquitinating enzymes (DUBs).s a signal for both proteasomal and lysosomal degra-roteins, and provide a scaffold for signal transduction.ulation has been shown to occur within LBs suggestinguse of the accumulation of alpha-synuclein into theseay be impaired autophagic ux (Tanaka et al., 2001).

ison with other neuronal populations that are in PD

rons of the SN are not the only ones to be affectedk et al., 2004; Del Tredici and Braak, 2012), do theseonal populations show any similarities with the neu-SN? Changes have been reported to also occur in several

stem nuclei including; the pedunculopontine nucleus

A. Reeve et al. / Ageing Research Reviews 14 (2014) 1930 27

Fig. 4. Age rel l deathoxidative dam ases ttoxic alpha-sy all thregion. Severa onal lin Parkinsons

(PPN), ventthe vagus nronal popuwhich maythe process2013). The tain neuromshow a lossshow alteradria in PD, sthese neuroin the largerons have band Lozanothese neuroease, but pr2012).

The cholin patients wthe SN at stof neurons also rely onA major conare the L-tyneurons shing activityneurons of in these neucontributiotherefore inthe VTA neuVTA have besynuclein, k2006). The dstem nucleigroup of nucin or neurthis patholo

Thereforteristics whthe uniquesignicantly

clus

h adv subspe mclinet of rprocumb

efcs. Ins an

thess mi

alphll losinor e madvanondrays hKomaated changes in a number of processes pushes substantia nigra neurons towards celage (through a number of processes) and accumulation of neuromelanin. This increnuclein or mitochondrial dysfunction leads to cell death. It is the accumulation ofl of these processes have been shown to be sufcient to cause substantia nigra neur

disease.

ral tegmental area (VTA), the dorsal motor nucleus oferve (DMV) and the locus coeruleus (LC). These neu-lations show similarities with the neurons of the SN

highlight not only their vulnerability in PD but alsoes key for the loss of SN neurons (Surmeier and Sulzer,medium sized neurons of the LC, for example, con-elanin, are noradrenaline containing, TH positive and

of around 70% in PD (Gesi et al., 2000). These neuronstions in the ultrastructure of their synaptic mitochon-uggesting mitochondrial alterations might occur withinns (Baloyannis et al., 2006). There is also a reduction

cholinergic neurons of the PPN, 50% of these neu-een reported to be lost in PD (reviewed in (Pahapill, 2000)). Interestingly LB pathology has been found inns in both Lewy body disease (LBD) and Alzheimers dis-ominent cell loss was only found in LBD (Dugger et al.,

inergic neurons of the DMV show Lewy body pathologyith PD at Braak stage 1, while pathology only appears in

age 3 (Braak et al., 2004). The vulnerability of this groupin PD has recently been investigated. These neurons

pacemaking activity, similar to the neurons of the SN.

6. Con

Wittion ofwild tytion deamounferent copy ntion inneuronneuronwithinsuch agatingthis ceAny mdamagwith amitochpathw2006; tributor to this activity within the neurons of the DMVpe CaV1.3 channels and similar to the SN neurons DMVow evidence of mitochondrial stress during pacemak-

(Goldberg et al., 2012). Furthermore, the dopaminergicthe VTA also show pacemaking activity, but the activityrons is modulated primarily by sodium with minimal

n from calcium channels (Khaliq and Bean, 2010). It isteresting that in comparison to the neurons of the SNrons are relatively spared, in addition the neurons of theen shown to be resistant to the overexpression of alpha-nown to cause the loss of SN neurons (Maingay et al.,evelopment of LB pathology in a number of other brain

has also been investigated and interestingly within thisclei only those which show an accumulation of lipofus-omelanin show an increased likelihood of developinggy (Braak et al., 1995, 2001).e vulnerable neuronal populations show some charac-ich are common to those of SN neurons, suggesting that

mixture of these features within the SN contributes to the development of PD.

age it is therons of the deciencies

Thereforcascade of weakens ththat are seedysfunctionsubsequentthey would

Acknowled

We woupreparationcastle Univby the BiotEngineeringSocial ReseaThe Wellco. These changes include accumulation of mitochondrial DNA defects,he vulnerability of the SN neurons so that a further insult from eitherese processes that will lead to the loss of neurons within this brainoss alone and so are likely to contribute to the death of these neurons

ion

ancing age a number of processes essential for the func-tantia nigra neurons including dopamine metabolism,itochondrial DNA copy number and protein degrada-

(Fig. 4). Dopamine metabolism generates a signicanteactive oxygen species that will affect a number of dif-esses within the neurons, a decline in wild type mtDNAer will lead to a decrease in ATP production and a reduc-ient protein degradation will affect the functioning of

addition accumulation of neuromelanin, the ability ofd mitochondria to handle calcium and the levels of irone neurons will also be affected, so that additional insultstochondrial complex I and IV deciencies and aggre-a-synuclein causes the loss of vulnerable neurons, onces reaches a certain level, the symptoms of PD develop.changes that affect this vulnerability to accumulatingy explain why not all individuals are affected by PDcing age. In isolation some of these processes includingial DNA mutations and changes in protein degradationave been shown to cause neuronal loss (Hara et al.,tsu et al., 2006; Reeve et al., 2013), but with advancing accumulation of many defects that renders the neu-SN vulnerable to the additional insults of mitochondrial

and toxic alpha-synuclein species.e, in conclusion we believe that ageing effects cause astressors within the substantia nigra which essentiallye neurons and their ability to respond to further insultsn as part of the disease process. Further mitochondrial

and alterations in protein degradation pathways arely far more detrimental to the neurons of the SN than

be to neurons elsewhere within the brain.

gements

ld like to thank Dr. Chris Morris for his help with the of this manuscript. This work was funded by the New-ersity Centre for Brain Ageing and Vitality (supportedechnology and Biological Sciences Research Council,

and Physical Sciences Research Council, Economic andrch Council and Medical Research Council [G0700718]),me Trust Centre for Mitochondrial Research [G906919]

28 A. Reeve et al. / Ageing Research Reviews 14 (2014) 1930

and the UK NIHR Biomedical Research Centre in Age and AgeRelated Diseases award to the Newcastle upon Tyne Hospitals NHSFoundation Trust.

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