Neurodegenerative diseases: model organisms, pathology ...

Journal of Genetics, Vol. 97, No. 3, July 2018, pp. 679–701 © Indian Academy of Scienceshttps://doi.org/10.1007/s12041-018-0955-3

REVIEW ARTICLE

Neurodegenerative diseases: model organisms, pathology and autophagy

S. N. SURESH1, VIJAYA VERMA2, SHRUTHI SATEESH2, JAMES P. CLEMENT2 andRAVI MANJITHAYA1,2∗

1Molecular Biology andGenetics Unit, and 2NeuroscienceUnit, Jawaharlal Nehru Centre for Advanced Scientific Research(JNCASR), Jakkur, Bengaluru 560 064, India*For correspondence. E-mail: [email protected].

Received 21 December 2017; revised 9 March 2018; accepted 20 March 2018

Abstract. A proteostasis view of neurodegeneration (ND) identifies protein aggregation as a leading causative reason for damageseen at the cellular and organ levels. While investigative therapies that aim at dissolving aggregates have failed, and the promises ofsilencing expression of ND associated pathogenic proteins or the deployment of engineered induced pluripotent stem cells (iPSCs)are still in the horizon, emerging literature suggests degrading aggregates through autophagy-related mechanisms hold the currentpotential for a possible cure. Macroautophagy (hereafter autophagy) is an intracellular degradative pathway where superfluous orunwanted cellular cargoes (such as peroxisomes, mitochondria, ribosomes, intracellular bacteria and misfolded protein aggregates)are wrapped in double membrane vesicles called autophagosomes that eventually fuses with lysosomes for their degradation. Theselective branch of autophagy that deals with identification, capture and degradation of protein aggregates is called aggrephagy.Here, we cover the workings of aggrephagy detailing its selectivity towards aggregates. The diverse cellular adaptors that bridgethe aggregates with the core autophagy machinery in terms of autophagosome formation are discussed. In ND, essential proteinquality control mechanisms fail as the constituent components also find themselves trapped in the aggregates. Thus, although cellularaggrephagy has the potential to be upregulated, its dysfunction further aggravates the pathogenesis. This phenomenonwhen combinedwith the fact that neurons can neither dilute out the aggregates by cell division nor the dead neurons can be replaced due to lowneurogenesis, makes a compelling case for aggrephagy pathway as a potential therapeutic option.

Keywords. neurodegeneration; aggrephagy; small molecule therapeutics.

Introduction

Cellular homeostasis is achieved through a balance ofanabolic and catabolic states. Cells possess severalquality control mechanisms to identify, correct orremove dysfunctional or potential toxic cellular compo-nents such as proteins and organelles. For example, insidethe cell, at steady state, misfolded proteins are formed con-tinuously and are fixed by chaperones or cleared throughthe ubiquitin proteasome system, and autophagy relatedpathways. This maintains the proteostatic equilibrium incells. Altered cellular states resulting from expression ofpathogenic levels or mutant forms of aggregate prone pro-teins overwhelm these quality control systems and theirbuild-up can eventually result in cell death. This is thefate of brain cells in neurodegenerative diseases (NDD).In this review, we unravel this proteostatic central view asa cause for ND, discuss the potential reasons behind the

failure of quality control systems with an emphasis on anaggrephagy, autophagy related pathway.

Proteostasis

Protein quality control machineries ensure the properfolding of newly synthesized proteins for their distinctfunction. This process is critical as 30% of these newproteins are prone to misfolding (Mymrikov et al. 2017).The cellular quality control measures include unfolding,refolding and/or degradation of the misfolded proteins(Sontag et al. 2017). Not surprisingly, failure of pro-tein quality control poses a threat to the cellular vitality(Balch et al. 2008). This qualitative process of maintain-ing the homeostasis of intracellular pool of functionaland ‘healthy’ proteins is called proteostasis. Proteosta-sis as a function for cell survival becomes even more

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680 S. N. Suresh et al.

critical for those cells such as neurons that cannot divideand thus dilute out the toxic protein aggregates (Balchet al. 2008). In addition, with age, the neuronal pro-teostatic machineries become incompetent and pronefor accumulation of damaged organelles and misfoldedproteins (Labbadia and Morimoto 2015; Walther et al.2017).

Protein misfolding is not an uncommon phenomenoninside cells. The presence of misfolded protein activateschaperones to unfold and refold them in an ATP-dependent manner. Misfolded proteins induce heat shockresponse (HSR) and heat shock (HS) transcriptionfactor HSF-1 that include the upregulation of heatshock cognate protein (Hsc70) (Kampinga and Craig2010). The aim of enhancing chaperone expressionand its activity is to prevent protein aggregation.Once the proteins remain misfolded despite theefforts by chaperones, they will form the higher orderstructures such as oligomers and aggregates that willeventually accumulate inside cells. In certain scenarios,when protein aggregates overwhelm the chaperone capac-ity, the available chaperones themselves get trapped inprotein aggregates (Anckar and Sistonen 2011; Ray-chaudhuri et al. 2014). Subsequently, these events alsoaggravate disease pathogenesis. An additional mecha-nism that has been recently described identifies misfoldedproteins as early as they are translating and subse-quently marks them for degradation. Such nascent mis-folded polypeptides are ubiquitinated at K-48 residueas a degradation mark in a process termed as cotrans-lational ubiquitination (CTU) (Wang et al. 2013). Thepolypeptide with this mark will be acted upon by pro-teasome for their effective degradation. CTU happenswithin the active translation complexes (Wang et al.2013).

At the organellar level, accumulation of misfolded pro-teins inside endoplasmic reticulum (ER) lumen inducesER stress, which triggers one of the vital cellular adaptivemechanisms known as unfolded protein response (UPR)(Powers et al. 2009). UPR leads to suppression of activeprotein translation, increase ER chaperone accumulationto unfold and/or degrade these proteins to amelioratethe proteotoxicity (Hetz 2012). Post-mortem brain anal-yses of Alzheimer’s disease (AD), Parkinson’s disease(PD) and Huntington’s disease (HD) have revealed thecorrelation of UPR markers with protein aggregationand onset of disease pathogenesis (Hetz and Mollereau2014).

The fate of misfolded proteins, not refolded bychaperones, are marked for degradation throughubiquitin-proteasome system (UPS) and/or autophagy.UPS degrades ubiquitinated, soluble and short-lived pro-teins. The target protein is tagged by ubiquitin throughthree enzymatic ubiquitin-activating (E1), ubiquitin-conjugating (E2) and ubiquitin-ligating (E3) reactions(Goldberg 2003). Ubiquitin is attached through its

carboxyl residue to specific lysine residue throughisopeptide linkage. One ubiquitin molecule is a targetfor another ubiquitin molecule and forms a polyubiqui-tin chain at its lysine residues at 48, 63 or at N-terminalmethionine residue (Kirkin et al. 2009). The polyubiquitinsignal at K-48 serves as a proteasome degradation signalwhereas K-63 and N-term methionine signals serve otherfunctions (Kirkin et al. 2009). It is also proposed thatK-63polyubiquitination may target a protein to autophagy, butthe exact mechanism is unclear.UPS has been shown to degrade several neurodegen-

erative disease related proteins such as tau, SOD1 andα-synuclein (Goldberg 2003). Inhibiting UPS accumulatedisease related proteins to aggregate and form inclusionbodies inside cells. Thus, UPS is essential for cells toprevent toxic protein aggregate formation (Lim and Yue2015). It is believed that larger aggregates that cannotbe resolved by UPS are the substrates of the autophagymachinery.

Aggrephagy: definition and modes

In 1960s, the Nobel laureate Christian de Duve observeddouble membrane vesicles entrapping intracellularorganelles and proteins, and coined the term ‘self-eating’or autophagy (De Duve andWattiaux 1966). Nobel laure-ateYoshinoriOhsumi tapped thepowerof yeast genetics toelucidate the molecular mechanism governing autophagyand contributed to the discovery of its conserved naturefrom yeast to mammals (Harnett et al. 2017).Depending on the distinct molecular mechanisms,

autophagy is broadly classified into three types: macroau-tophagy, microautophagy and chaperone-mediated auto-phagy (CMA). Macroautophagy is the most extensivelystudied process that has an indispensable role in maintain-ing cellular andorganismal homeostasis.Duringmacroau-tophagy, a phagophore or isolation membrane forms andfurther expands to form double membrane autophago-somes that engulfs cellular cargoes. These cargoes are partsof cytosol constituting superfluous organelles, pathogenicorganisms, misfolded protein aggregates and/or dam-aged mitochondria (Zaffagnini and Martens 2016). Theseautophagosomes fuse with lysosomes to form autolyso-somes and eventually degrade its intraluminal cargoes.The degraded entities result in building blocks that arerecycled back to the cytosol for fuelling other cellularpathways. Apart from randomly sequestering portions ofcytosol for degradation (general autophagy), macroau-tophagy can be highly selective in the cargoes it captures.The selective autophagy pathway that is involved in clear-ance of misfolded protein aggregates is called aggrephagy(Hyttinen et al. 2014). Here, misfolded proteins that aretagged by ubiquitin are recognized by adaptor proteinssuch as p62, NBR1 and NDP52 which in turn recruitautophagy proteins such as LC3 to facilitate selective cap-ture (figure 1). Thus, aggrephagy is a prominent defense

Neurodegenerative diseases 681

Figure 1. Formation of aggrephagosome. Aggregate proteins are ubiquitinated (Ub) which are recognized by adaptor proteins. p62,NDP-52, NBR1 and optineurin are some of the examples of adaptor proteins that have a ubiquitin-binding domain and additionallyhave LC3 interacting region (LIR) that can recruit LC3 and thereby facilitate cargo recognition and capture.

mechanism against misfolded protein aggregate-mediatedcellular toxicity. Microautophagy is the direct uptakeof cargo by lysosomes through membrane invagination.Chaperone mediated autophagy (CMA) is the selectivedegradative process of proteins that involves Hsc70 butis a vesicle independent process. During CMA, the targetprotein is recognized by Hsc70 through a specific aminoacid motif, KFERQ and delivered to lysosome by inter-acting with LAMP2A in an ATP-dependent manner.

Synaptic dysfunction in NDD

Synaptic plasticity refers to the ability of synapses tomodify their structure and tonus after persistent elec-trical activity and/or signalling. In fact, the number,morphology, position, molecular phenotype and strengthof synapses continue to modify as a function of neurons’requirements. These events take place in the nervous sys-tem during its development, which represents the basis forlearning and memory (Bliss and Collingridge 1993; Citriand Malenka 2008). In case of neurons, in addition to theautophagy process in soma, autophagy occurring at thesynapse, of late, has received much attention as it involvesimmediate turnover of proteins and, thus, affects synap-tic transmission. Mutations in genes involved in severalneurodegenerative diseases such as AD, HD, ALS and

PD affect synaptic proteins levels and functions (Lepetaet al. 2016). Synaptic dysfunction throughout the centraland peripheral nervous systems has shown to be an earlyhallmark of neurodegenerative diseases preceding neu-ronal death and the subsequent onset of clinical symptoms(figure 2; table 1) (Brose et al. 2010). These events have beenvalidated using transgenic mouse models available for dif-ferent neurodegenerative diseases (Trancikova et al. 2011).

Neurodegeneration model systems as tools to studyaggrephagy

Numerous model systems have been utilized to study theaggrephagy and modulate it to clear the protein aggre-gates. It is important to note that the cellular proteostaticmachineries are conserved from simple yeast to highermodel rodents. We will briefly discuss the different modelsystems used to understand the neurodegeneration patho-genesis with a special emphasis on autophagy.

Animal models to study NDD

Historically, mouse has been used as a model to studygenetic mutation-causing diseases in humans, especially


Figure 2. Signalling pathways affected in neurodegenerative disorders. Schematic to show impaired synaptic function due to alteredfunction of different signalling pathways in different neurodegenerative disorders. Presence of aggregates in these diseases leads to anincrease in presynaptic release of glutamate orDAupon stimulation that activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid receptor (AMPAR), DA receptor1 (D1R) and DA receptor2 (D2R), respectively. (a) Activation of AMPARs leads toN-methyl-D-aspartate receptors (NMDAR) activation which is followed by Ca2+ influx. Additionally, voltage gated Ca2+ channel(VGCC) further facilitates the Ca2+ influx leading to an increased intracellular Ca2+ levels at the postsynapse. This increased levelsof Ca2+ results in: (1) excitotoxicity, (2) mitochondrial dysfunction, (3) reactive oxygen species (ROS) activation, (4) CASPASEactivation, (5) apoptosis, and 6) mTOR activation (autophagy inhibition). These events eventually result in neuronal dysfunction,neurodegeneration, and cognitive impairments. (b) Stimulation of metabotropic glutamate receptor5 (mGluR5) by glutamate leadsto activation of inositol 1,4,5-trisphosphate (IP3). In neurodegeneration, the aggregates strongly bind to the IP3 receptor1 (IP3R1),which results in the release of the Ca2+ through IP3R1, in turn, further contributing to already increased intracellular Ca2+ levels,resulting in synaptic dysfunction. (c) DA acting on DA1 receptor activates adenosine 3′,5′-cyclic monophosphate (cAMP), whichfurther activates protein kinase A (PKA). Upon PKA activation, the intracellular Ca2+ levels increase through IP3R1. Addition-ally, PKA activates DA-regulated and cAMP-regulated neuronal phosphoprotein (DARRP-32) and extracellular signal-regulatedkinases (ERK), which alters cAMP response element-binding protein (CREB) activity resulting in altered transcription and cognitiveimpairment. (d) DA acting on DA2 receptor further contributes to the intracellular Ca2+ levels through the activation of IP3R1.This Ca2+ influx simultaneously activates CALCINEURIN followed by glycogen synthase kinase 3 β (GSK-3 β) activation, leadingto the phosphorylation of TAU. This event results in impaired cognition and cell death.

brain related disorders including neurodegenerationdiseases, due to the similarity of mammalian neuronalphysiology and anatomy to human brain. The main ratio-nale to model human disorders in nonhuman organisms isthe identification of fundamental pathogenic mechanismsthat could lead to potential novel therapeutic targets, andthe elevation of efficacy and safety of potential drugs. Aprerequisite for clinical trials of a compound in humansis the successful alleviation of the disease or symptoms inanimal models.The occurrence of neurodegeneration is majorly a spo-

radic event with poorly understood aetiological basis.However, in familial cases of AD, PD, HD and ALS,

the genetic mutations are the underlying causes of diseasephenotypes and these can be recapitulated in animal mod-els. Due to a rapid increase in the availability of the type ofgenetically modifiedmice (Branchi et al. 2003), it is criticalto meticulously characterize the biochemical, pathologi-cal and behavioural features of these mice and comparethem with human phenotypes (Crawley 2008). Generally,laboratories involved in testing the phenotypes of genet-ically modified mice subject these mice to a battery ofbehavioural features to assess cognitive, motor and sen-sory functions. To consider a genetically modified mouseas a disease model, it must fulfil three levels of validityto judge its psychopharmacology (van der Staay et al.


Table

1.Su

mmaryof

syna

pticdy

sfun

ctionob

served

indifferentneurod

egenerativediseases.

Properties

ALS

PD

AD

HD

Basal

syna

ptic

tran

smission

(BST

)

Impa

ired

tran

smission

((↓)

presyn

apticrelease)

(Maselli

etal.1

993)

Una

ltered

inmedium

spiny

neuron

s(M

SN’s)

ofLRRK2

over

expressing

mice

(Beccano

-Kelly

etal.2

015)

Altered

BST

was

observed

inApp

695S

wemutan

t,Apoe4

mice(↑),App

Indmice(↓)

(Hsiaet

al.1

999;

Filimon

enko

etal.2

010;

Puzzo

etal.2

017;

Sunet

al.2

017)

InR6/2,

BST

isaltered(↓)

(Cepedaet

al.2

001;

Klapstein

etal.2

001;

Miln

erwoo

det

al.

2006;K

hedrak

ietal.2

017)

Neurotran

smitter

release

Increase

inglutam

ate-indu

ced

excitotoxicity;p

resyna

ptic

tran

smission

deficit(C

oyle

andSchw

arcz

1976;L

ipton

andRosenberg

1994;D

oble

1999;K

iernan

etal.2

011)

Deficiency

ofdo

paminein

the

nigrostriatalsystem,a

ndin

levelsof

somatostatin

(Rinne

etal.1

984)

SVtrafficking

defects(E

spositoet

al.2

012)

Increasedpresyn

apticfunction

(Sun

etal.2

017)

InR6/2,

alteredpresyn

aptic

release(↓),po

sttetanic

potentiation

(↓),an

din

YAC12

8in

12mon

ths(↓)

(Murph

yet

al.2

000;

Cepeda

etal.2

001;

Klapstein

etal.

2001;M

ilnerwoo

det

al.2

006;

And

reet

al.2

011;

Khedrak

iet

al.2

017)

Increasedactivity

ofGABA

and5-HTT(A

nden

1974;

Grabo

wskaan

dMicha

luk

1974;M

ajet

al.1

974;

Hollisteret

al.1

976)

Syna

pticplasticity

Impa

ired

LTPin

Ubqln2P

497H

andSod

1mice

(Geracitan

oet

al.2

003;

Gorrieet

al.2

014)

LTPob

served

inoriginal

LTD-ind

ucingstim

ulus

(Kreitzeran

dMalenka

2005;

Bagetta

etal.2

010)

LTPin

AAV-A

pp/Ps1

(↓),

Apoe4

(↓)(A

udrain

etal.

2016;P

uzzo

etal.2

017;

Sun

etal.2

017)

Impa

ired

LTPan

dLT

Din

R6/2(M

urph

yet

al.2

000)

Cellintrinsic

prop

erties

Altered

excitabilityan

daltered

fastafterhyp

erpo

larization

(fAHP)an

dslow

afterhyp

erpo

larization

(sAHP)in

Sod

1(↑),Tardbp

(↓),Ubqln2P

497H

(↓),

Sod

1A4V

(↑)mice(F

ischer

etal.2

004;

Murrayet

al.2

010;

Zho

uet

al.2

010;

Waing

eret

al.2

014;

Rad

zickietal.

2016;K

imet

al.2

017)

Increasedpo

stsyna

ptic

potentials,intrinsicmem

bran

eprop

erties,p

ostsyn

aptic

respon

sesto

differentagon

ists

ofexcitatory

aminoacid

receptorsno

talteredin

neuron

srecorded

from

dopa

mine-depleted

slices

(Calab

resiet

al.1

993)

Highlydisorgan

ised

syna

pses,

increasedan

ddispersedtonic

glutam

atergiccurrent

amplitud

ein

AAV-A

pp/Ps1

(Aud

rain

etal.2

016)

Altered

inpu

t,resting

mem

bran

epo

tentials,tim

econstantsan

daction

potentialsin

CAG40

KI(↓),

R6/2(↓)an

dYAC128(↓)

(Levineet

al.1

999;

Klapstein

etal.2

001;

Graha

met

al.

2009;C

ummings

etal.2

010)

IncreasedNMDA/A

MPA

ratio

(Hsiaet

al.1

999)

Decreased

inthefrequencyof

mEPSC

andno

chan

gein

amplitud

eon

applicationof

Amyloid-

βin

culture(Y

uet

al.2

012)


Table

1(contd)

Properties

ALS

PD

AD

HD

Regions

invo

lved

Motor

cortex

upperan

dlower

motor

neuron

s,Brain

stem

andSp

inal

cord

(Ago

staet

al.

2010;K

umar

etal.2

011)

Substantia

nigra,

Putam

enCau

date

nucleus,Globu

spa

llidu

san

dCerebralcortex

(Sianet

al.1

994)

Initially

entorhinal

cortex,

hipp

ocam

pusan

dlater

cerebral

cortex

buteventually

allregions

areaffected

Prefron

tal,motor

andStriatum

(globu

spa

llidu

san

dthe

substantia

nigrapa

rsreticulate).HTTan

dmutan

tHTT(m

HTT)proteins

expressedub

iquitously,

predom

inan

tlyin

thestriatum

Receptors

and

neurotransmitters

invo

lved

Acetylcho

linereceptors

(AChR

s)(Palmaet

al.2

016).

Glutamatereceptor

(Pau

land

Belleroche2014)Lossof

metab

otropicglutam

ate

receptor-m

ediatedregu

lation

(Vermeirenet

al.2

006)

Cho

linergic-muscarinic

receptorsGABA

receptor

(Rinne

etal.1

984)

Overactivationof

glutam

ate

receptors(Bergm

anet

al.

1994;H

assani

etal.1

996)

Nicotinican

dmuscarinic

acetylcholinereceptors

(Kiharaan

dSh

imoh

ama

2004)Cytok

inereceptors

(Nagae

etal.2

016).N

MDA

receptor

andGlutamate

(Dan

yszan

dParsons

2012).

Dop

amine(M

artorana

and

Koch2014)

NMDA

receptor

(Levineet

al.

1999;P

aolettietal.2

008).

mGluR’s(group

2,3),A

MPA

,Kaina

te,D

opam

ine,

Muscarinican

dGABA

Receptors

(Cha

etal.1

998;

Sepers

andRaymon

d20

14)

Dop

aminergicD1-lik

ereceptors,substanceP(SP)

anddy

norphinan

dD2-lik

ereceptorsan

dmet-enk

epha

linareim

plicated

(Hab

eran

dNau

ta19

83;A

ndre

etal.

2010).Im

paired

dopa

mine

andglutam

ateho

meostasis

(And

reet

al.2

010)

Chrom

osom

e/genes

invo

lved

21q2

2.1SO

D1

2q33

-2q3

5Alsin

9q34

SETX

15q1

5-21

SPG

1116

p11.2FUS

20q1

3.3VA

PB

14q1

1.2ANG

6q21

FIG

41p

36.2

TARDBP10

p13

OPTN

9p13

.3VCPXp1

1UBQLN2

9p21

C9O

RF72

(Chenet

al.

2013)

4q21

SNCA

12q1

2LRRK2

APP(21q

21.3)(Yoshika

ietal.

1990;T

hina

karanan

dKoo

2008).PSEN1(14q

24.3)

(Esler

andWolfe

2001

).PSEN2(1q4

2.13

)(Steiner

2004)

4p16

.3chromosom

alfragment

containing

IT15

gene

6q25

–q27

Parkin1p

35–p

36PIN

K11p

36DJ-11p

36ATP13

A2(L

esagean

dBrice

2009)

(↓)or

(↑)indicatesdecrease

orincrease

inthat

specificprop

erty

inthesaid

mou

semod

el,respectively.


2009).Ananimalmodel should score highon the followingvalidities: face validity, i.e., resemblances of behaviouralphenotypes of mouse model to that of human disorder;construct validity, i.e., closely reconstructs and mimics theunderlying cause of the disease or disorder; and predic-tive validity, i.e., treatments alleviate symptoms in mouseand human. A successful mouse model should fulfil faceand construct validity before being tested for therapeutics(predictive validity). Due to these varied features and theirbehavioural readouts, the mouse models of the respectivehuman diseases are highly useful in NDD research and inpreclinical studies.

Parkinson disease

PD is characterized by progressive degeneration of nigros-triatal dopaminergic neurons, leading to loss of motorfunction, rigidity, postural instability, tremor, andbradyki-nesia as described in the 1800’s by JamesParkinson (Mhyreet al. 2012; Rouse et al. 2000). Both familial (5–10% ofall cases) and acquired (90–95% of all cases) forms ofParkinsonism are usually caused by defects in dopamine(DA) metabolism. Decrease in DA inputs from basal gan-glia (BG) result in impaired control of motor circuitsthat ultimately leads to clinical symptoms (Spillantiniet al. 1997). For the PD mouse model, the transgen-ics express pathogenic mutant version of PD associatedgenes such as α-Synuclein, Parkin, Pink1 and Park7. α-Synuclein transgenic mice exhibit Lewy bodies that arethe histopathological hallmark of PD. These animals exertage-related progressive movement deficits, which is associ-ated with dopaminergic neuronal loss. However, not alltransgenic mutants exert significant dopaminergic neu-ronal loss.Activity-dependent modifications in synaptic efficacy,

such as long-term depression (LTD) and long-term poten-tiation (LTP) represent the key cellular substrates foradaptive motor control and procedural memory (Blissand Collingridge 1993). DA acting on D1-like and D2-like receptors play a critical role in driving the above-mentioned forms of synaptic plasticity in striatum. D1and D2 receptor signalling pathways converge in oppositemanners on a common target, DARPP-32. The involve-ment of DA in these phenomena has been thoroughlyestablished by the study of synaptic plasticity in striatalneurons recorded from rodent models of PD (Calabresiet al. 1992a,b). The absence of synaptic plasticity andabnormal synapse structure implied the cellular basisunderlying the abnormalities in striatal output within theBG, and consequently resulting in PD symptoms.Abnormalities in the subcellular distribution of N-

methyl-D-aspartate receptor (NMDAR)subunitGRIN2Brepresent one of the major changes that take placeat corticostriatal glutamatergic synapses. In fact, stud-ies using dyskinetic mouse models, increased levels of

GRIN2A and lower levels of GRIN2B were observed inextrasynaptic sites which altered binding ofNMDAR sub-units with their cargo proteins such as Synapse-associatedprotein 97 (SAP97) and SAP102 (Gardoni et al. 2006;Sheng and Sala 2001).Moreover, activation ofDARPP-32(DA-regulated and cAMP-regulated phosphoprotein-32)results in increased opening of the L-type Ca2+ chan-nels promoting the transition of medium spiny neurons(MSN) to a higher level of excitability, which in turnsphosphorylates AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDARs providing amechanism for the direct control of glutamatergic trans-mission byDA signalling, that is altered in PD (Greengardet al. 1998; Vergara et al. 2003). This is further evidentfrom the studies that show the DA-denervation augmentsneuronal excitability in the striatum leading to excitabilityof striatal neurons, which is caused due to the increasedglutamatergic cortical inputs to the striatum (Calabresiet al. 1993; Centonze et al. 2004). The increased glutamatelevel in the synaptic cleft (Herrera-Marschitz et al. 1994) isconsequently responsible for the overactivity ofNMDARsand AMPARs on MSNs, which correlate with the motorbehaviour abnormalities observed in a rat model of PD.Thus, functional changes of the striatal neurons may alterthe output signals from the striatum to the other struc-tures of the BG that leads to pathophysiological changesobserved in PD.Evidences also suggest that the genes linked toPDplay a

critical role in regulating proper presynaptic and synapticvesicular transport, modification of DA flow and alteredpresynaptic plasticity (Dihanich andManzoni 2011).OnceParkinsonism is well established, i.e. parkinsonian state,most BG mechanisms are insufficient and cortical mech-anisms become important (Dihanich and Manzoni 2011;Blesa et al. 2017). At the postsynaptic level, decreased acti-vation of D2 receptors leads to a disinhibition of voltage-gated ion channels and increased influx of Ca2+ that leadsto degeneration of the synapses observed in PD-affectedanimals and in PD patients (Nitsch and Riesenberg 1995;Arbuthnott et al. 2000; Calautti et al. 2007). In DA-denervated striatum, NMDAR subunit GRIN1, and itsinteracting protein at synapse, PSD-95, levels are selec-tively reduced in the postsynapse (Lundblad et al. 2004).

Amyotrophic lateral sclerosis

ALS is a devastating neurodegenerative disease charac-terized by progressive loss of upper motor neurons in themotor cortex (cortical layer of pyramidal cells of corticallayer V), and of lower motor neurons in the brainstem andspinal cord as first described by Jean-Martin Charcot in1869 (Kumar et al. 2011). ALS typically affects adults inmid-life, with an incidence of 1–2 per 100,000 per year(Rosen 1993). Most ALS patients have no affected fam-ily members and are considered to have sporadic ALS.


Familial ALS occurs in 5–10% of cases and hasbreak anautosomal dominant inheritance.Mutations in genes suchas TARDP (TDP-43), FUS and SOD1 drive the famil-ial forms of ALS. In 20% of familial cases, mutations inthe superoxide dismutase-1 (SOD1) gene on chromosome21q were identified (ALS1) (Rosen 1993). The recessive,juvenile ALS2, is caused by mutations in ALSIN, whichcodes for a protein containing guanine exchange factordomains (Hadano et al. 2001; Yang et al. 2001). Micetransgenics overexpressing wild type or mutant TDP-43proteins cause TDP-43 inclusion bodies and loss of motorneurons with behavioural impairments. In addition, miceoverexpressing mutant SOD-1 develops inclusion bodies,neuronal loss, gliosis, tremor, hindlimb paralysis with sig-nificant decrease in lifespan.The pathological hallmark of ALS is the degeneration

of lower motor neurons in the brainstem and spinal cord,upper motor neurons in the motor cortex, and of the cor-ticospinal tracts, accompanied by reactive gliosis (Peharet al. 2005). The exact pathogenic mechanism underly-ing the selective motor neuron death in ALS is yet to beelucidated, although many possible mechanisms in spo-radic ALS, and SOD1-linked ALS have been proposed(Brown and Robberecht 2001; Cleveland and Rothstein2001; Julien 2001; Heath and Shaw 2002). One of the com-mon reasons for neuronal degeneration is because of theoverstimulation of glutamate receptors induced excitotox-icity (Lipton and Rosenberg 1994).

Evidences from the previous studies have strengtheneda link between glutamate-mediated toxicity and sporadicALS. Motor neurons express Ca2+-permeable AMPARs,GRIA2 subunit, and are, therefore, particularly vulnera-ble toAMPAR-mediated excitotoxicity (vonLewinski andKeller 2005). Transgenic mice expressing GRIA2 subunitswith an asparagine at the Q/R site (conferred a two-foldincrease in the Ca2+ permeability of AMPARs) (Feld-meyer et al. 1999), and showed late-onset of degenerationof spinal neurons and a decline in motor function (Kuneret al. 2005). Crossing these mice with those carrying amutation linked to familial ALS accelerated disease pro-gression and motor decline (Kuner et al. 2005), and thephenotype is exaggerated when GRIA2 is deleted (VanDamme et al. 2005).

The NMDAR-mediated neurotoxicity and subsequentoverload of mitochondrial Ca2+ and ROS productionhas been shown to take place in cultured motor neu-rons (Carriedo et al. 2000). Further, the NMDAR/Ca2+mediated excitotoxicity has been demonstrated in theneuronal loss observed in spinal neurons obtained fromhuman low molecular weight Neuro filament (NF) pro-tein (hNfl+/+) mice, an ALS mouse model (Nicholls et al.2007; Sanelli et al. 2007; Kambe et al. 2011). Compellingevidence supports the fact that excessive Ca2+ influxthrough NMDARs targets mitochondria which resultsin excitotoxicity in ALS-related MN death (Peng et al.1998). It is intriguing to hypothesize that regain control

of the NMDAR functionality will in turn affect AMPARfunction, due to the close interaction between these recep-tors, thereby further hampering the ALS-related excito-toxic drive.Apart from the extensive loss of motor neurons, there is

degeneration of midbrain dopaminergic cells and reducedtyrosine hydroxylase positive neurons which has beendescribed in both familial and sporadic forms of ALS(Andreassen et al. 2000; Kostic et al. 1997), and functionalalteration of the voltage-dependent Na2+ channel (Zonaet al. 1998). The dysfunction in the DA neurons is shownby investigating the corticostriatal synaptic plasticity inmice overexpressing the human SOD1 and mutating the(Gly933Ala) form (G93A) of the same enzyme (Lovingeret al. 1993; Calabresi et al. 2000).

The pivotal role of DA in corticostriatal LTD is wellestablished. For example, injection of 6-hydroxydopaminein rodent model leads to DA denervation that modifies thecorticostriatal plasticity (Calabresi et al. 1992a,b). More-over, a decreased striatal D2 receptor binding in sporadicALShas been described and is likely to occur because of anexcessive glutamatergic corticostriatal neurotransmission(Vogels et al. 1999, 2000). This pattern of degenerationis consistent with the observation that elevated levels ofSOD1 are expressed in BG cells, including the midbraindopaminergic neurons (Pardo et al. 1995). In conclu-sion, perturbations in these systems may cause the cell tobecome more susceptible to excitotoxic damage.There is spectrum of synaptic changes that occur in

ALS during the process of anterior horn neuron degen-eration. One such probable cause is due to the decreasesin cell body area, number of synapses, and synaptic con-tact length which is evident even during the early stage ofthe disease. It is noteworthy that despite decreases in cellbody area, synaptic numbers and synaptic contact length,the length of the active zone was not reduced in the nor-mally appearing neurons of the ALS patients (Sasaki andMaruyama 1994). The continuous loss of synapses thatis observed from myriad studies implies a decrease in theglobal connectivity of the motor system and a decreasedpotential for motoneuronal interaction.Theneuromuscular junction (NMJ) is the synapsewhere

the axon terminal of a motor neuron (MN) meets themotor endplate. Recent studies suggest that distal degen-eration in the skeletal muscle plays a key role in theprogression of ALS. Several studies using SOD1G93Amice have shown that NMJ degeneration occurs in theinitial stages of disease progression, long before MN loss(Brooks et al. 2004; Fischer andGlass 2010;Kanning et al.2010).

Huntington’s disease

HD is a progressive neurological disorder characterizedby chorea (uncontrolled dance like movement), cognitive


disturbances, depression and other psychiatric symptoms(Harper 1996). It is inherited in an autosomal dominantfashion, and severity of the disease depends on numberof CAG repeats (Jones et al. 1997; Walker 2007). BothHTT and mutant HTT (mHTT) proteins are ubiquitouslyexpressed, predominantly in the striatum, although it isthe least affected in HD, and in moderate levels in otherparts of the brain (Bhide et al. 1996). HTT is shown tobe expressed in the brain from midgestational period, andthe expression of mHTT was observed as early as 10-weekold infant’s brain suggesting an implication for proper neu-ronal development and function, especially when the brainis vulnerable to excitotoxic injury (DiFiglia 1997).

To further understand the function of HTT and mHTTin normal neuronal function and in diseased states respec-tively, several mouse models of HD has been created(Menalled and Chesselet 2002; Levine et al. 2004; Cepedaet al. 2010; Menalled and Brunner 2014). There are twotypes of mouse models of HD: ‘transgenics’, in which themutant gene or part of it, is inserted randomly into themouse genome, leading to the expression of mutant pro-tein along with the endogenous normal HUNTINGTIN;and ‘knock-ins’, in which the mutant gene is inserted intothe mouseHdh (mouseHuntington) gene, leading to eitherhomozygotes or heterozygotes for the mutation (for fur-ther informationplease referMenalledandChesselet 2002;Menalled and Brunner 2014). Myriad of transgenic micewith expanded polyQ repeats like R6/1, R6/2 and N171-Q82 have been generated that recapitulate the symptomsof HD. All these models develop aggregate inclusions,neuronal loss and motor-coordination deficits. The firstand most widely used transgenic mouse model of HDwas generated by overexpression of exon 1 of the humangene encodingHUNTINGTIN(IT15)with141-157CAG-repeat expansions, which was termed as R6 (Mangiariniet al. 1996). Unlike Htt homozygous knock-out (KO)(embryonically lethal but notHtt conditional Knock-out)(Nasir et al. 1995; Wang et al. 2016), R6 mice survive for13 weeks. Apart from the motor deficits, these differentmouse models exhibit altered synaptic function and cog-nitive deficits.Researchovermany years suggests that cognitive defects

appear long before the onset of overt motor dysfunctionin HD (Paulsen et al. 2008). These studies have shown thatsynaptic dysfunction precedes cell death by many yearsin humans (Murer et al. 2002). It is observed that loss ofmedium-shaped spiny (MSN) projection neurons in stria-tum, and pyramidal neurons from cortex is considered asprominent pathological characteristics of HD (Von sattelet al. 1985; Milnerwood et al. 2010; Milnerwood and Ray-mond 2010).

Impaired DA homeostasis is one of the major conse-quences ofHTT (includingHtt) mutation that contributesto the impaired information processing from the corti-cal inputs to striatum (Andre et al. 2010). Dopaminergicneurons from substantia nigra and ventral tegmental

area (VTA) project to the dorsal striatum to regulateglutamatergic neurons (direct pathway; rich in D1 recep-tors; facilitates movement), whereas, indirect pathwayprojects to external globus pallidus (rich in D2 recep-tors; suppresses movement) (Andre et al. 2010; Sepersand Raymond 2014), which are found to be degeneratedin HD. On the contrary, Andre et al. (2010) have shownthat hyperactivation of the nigrostriatal pathwaymay elicitthe characteristics of chorea observed in HD. Therefore,agents affecting dopamine transmission are used to mod-ulate HD (Murer et al. 2002).

Proper glutamatergic function of these neurons is drivenmajorly by glutamate (excitatory neurotransmitter), and,thus have an increased sensitivity towards NMDARactivation leading to neuronal death, especially in HD(McGeer et al. 1977; Fonnum et al. 1981; Schwarcz et al.1983). By the timemotor symptomswere observed,major-ity of striatal glutamatergic neurons and spine densitieswere lost (Li 1999;Cepeda et al. 2007, 2010). Thus, reducedglutamatergic signalling in the striatum could lead to lossof spines and, eventually, contribute to motor deficits.To study the functional insights of HD pathology, elec-

trophysiological studies have dissected out intrinsic andsynaptic neuronal properties (Sepers and Raymond 2014).Studies have shown that, in R6/2 mice, basal synaptictransmission and presynaptic release were progressivelyaltered (Cepeda et al. 2001; Klapstein et al. 2001; Milner-wood et al. 2006; Khedraki et al. 2017). PresymptomaticR6/2 mice showed increased neuronal input resistanceand lower stimulus intensity to evoke action potentials(rheobase), whereas, symptomatic R6/2 mice exhibitedincreased resting membrane potentials, input resistanceand decreased membrane time constants and synapticplasticity. Taken together, these findings indicate that pas-sive and active membrane and synaptic properties ofmedium-sized spiny neurons are altered in the R6/2 trans-genic.Many studies have observed an early augmentation of

NMDAR activity in MSNs of HD mouse (Milnerwoodand Raymond 2007; Cepeda et al. 2010; Cummings et al.2010). Further, overexpression of GluN2B subunit in HDhas been shown to exacerbate the phenotype and pathol-ogy. Studies have shown that brief stimulation of synapticNMDAR (containing GluN1/GluN2A) leads to survivalsignalling via brain derived neurotrophic factor (BDNF)activation (Martire et al. 2013) but activation of extrasy-naptic NMDAR (containing GluN1/GluN2B) is neuro-toxic and leads to cell death (Hardingham et al. 2002).These studies suggest that hyperactivation of extrasynap-tic NMDAR leads to neuronal loss in HD.In another mouse model of HD, yeast artificial chro-

mosome (YAC)-Htt (YAC128), containing entire humanHTT to have 128 CAG-repeat expansions (Slow et al.2003), it was found that the probability of release at D1-presynapse was increased in 1.5 months, but decreased at12 months. However, D2-presynapse release probability


was not altered in these mice (Cummings et al. 2010).Further studies have shown that the synaptic transmis-sion and function are altered in YAC128 mouse model ofHD (Miller et al. 2008; Joshi et al. 2009). Similar obser-vations were found in other mouse models of HD (Levineet al. 1999, 2004; Klapstein et al. 2001; Graham et al. 2009;Pouladi et al. 2009; Cummings et al. 2010; Akopian et al.2016; Kolodziejczyk and Raymond 2016).

Alzheimer’s disease

AD is the most common cause of senile dementia anda devastating neurodegenerative disease. Formation ofsenile plaques, neurofibrillary tangles, massive loss ofsynapses, and eventual neuronal cell death are the patho-logical hallmarks of AD. The pathogenesis is associatedwith increased β-amyloid (Aβ) levels in the brain generatedby proteolysis of amyloid precursor protein (APP) withthe help of Presenilin1 (PSEN1), and part of γ- secretasecomplex (Strooper et al. 1998; Selkoe 2002). Mutations inAPP and Presenilin1 or both genes result in an autosomaldominant form of AD. To understand the mechanism ofAD, temporal evolution, and to translate it for therapeuticpurposes, several transgenicmousemodels ofADhas beenused till date. There are currently 127 animalmodels ofADin use having wide variety of mutations (single, double andtriple mutations) that are implicated in AD (Higgins andJacobsen 2003; LaFerla and Green 2012; www.alzforum.org). Recently, very robust mouse model, 5xFAD, hav-ing five familial AD mutations, causes relatively early andaggressive presentation of AD, has been widely used ascompared to other models. It recapitulates the followingdisease phenotypes: β-amyloidosis, plaques, neurite dys-trophy, dendritic spine loss, neuroinflammation, neuronalloss and age-dependent cognition decline. Following arethe limitations of this models: (i) evidences from positron-emission tomography (PET) suggest that mouse plaquesare significantly differ from human biochemically, and (ii)another caveat is the neuronal loss is not profound as thatof humans (Sasaguri et al. 2017). A detailed review onvarious animal models of AD can reviewed here (LaFerlaand Green 2012; Pozueta et al. 2013; Sasaguri et al. 2017).These transgenic models show synaptic dysfunction, and,thus, provide an opportunity to understand the mech-anisms of neurophysiological deficits observed in AD,mainly the synaptic and cognitive decline (Rowan et al.2003; Spires-Jones and Knafo 2012). Abnormalities insynaptic function in AD was observed more than fourdecades ago by Gonatas et al. (1967). Since then, thereare many studies that focussed on reinforcing the idea thatloss of synaptic function is the main characteristics of AD.Indeed, this was further confirmed by quantitative ultra-structural and immunohistochemical post-mortem studiesfrom human AD patients with symptoms ranging frommild-cognitive impairments to early-mild AD (Masliah

et al. 1989; Terry et al. 1991; Scheff and Price 1993). Mostof the electrophysiological studies of amyloid depositingmouse models have investigated alterations in synapticstrengthbetweenhippocampalpyramidal neuronsbymea-suring basal synaptic strength, synaptic transmission, andneuronal intrinsic properties (Nistico et al. 2012). A studyfrom a mouse model of AD expressing single or doubletransgenic mutations showed normal basal synaptic trans-mission but impaired LTP in early stage of AD (Liu 2008),while in another study using App695Swe mutation, nor-mal LTP with deficits in basal synaptic transmission wasobserved for both 12-month as well as 18-month old mice(Fitzjohn et al. 2001). These initial studies have shown thatdisruption in synaptic function is themajor cause of cogni-tive decline in AD. Studies have shown that AD pathologyincreases in an age dependant manner (Hsia et al. 1999;Sun et al. 2017). By using Apoe4mouse (four months andolder), alteration in short as well as long-term plasticityhas been observed (Sun et al. 2017). A similar age depen-dent decline in basal synaptic function was observed inother models (Hsia et al. 1999; Puzzo et al. 2017). Thesestudies clearly show that the decline in basal synaptic func-tion is an early indicator cognitive decline observed in laterstages of AD. To further understand whether amyloido-genic processing of APP is responsible for amyloid-β andtau toxicity, toxic proteins are administered in acute brainslices prepared from wild type (WT) as well as BACE1KO mice. No affect in basal synaptic transmission wasobserved inWT or BACE1 (β secretase) KOmice but LTPwas impaired in both genotypes, suggesting that the toxi-city did not depend on APP processing alone (Puzzo et al.2017). Apart from the alterations in synaptic function,abnormal dendritic spine structures were also observed inAD.Dendritic spines are specialized anatomical structureson neuronal cells that serve as the postsynaptic componentfor the excitatory dendritic spines. Several studies usingdifferent mouse models of AD have identified severe den-dritic spine loss and plaque-associated structural plasticitydeficits in AD. This is extensively reviewed here (Rowanet al. 2003; Spires-Jones and Knafo 2012; Pozueta et al.2013). Based on these studies, basal synaptic function canbe used as a biomarker to detect AD in an early stage ofdevelopment.

Drosophila melanogaster

It is a multicellular eukaryote that exhibits both histo-logical and behavioural phenotype associated with neu-rodegeneration. Flies expressing the proteins such asα-synuclein, β-amyloid, polyglutamine repeat, tau reca-pitulate many of the histological and behavioural diseasephenotypes associated with neurodegeneration. In thismodel, the toxic proteins are overexpressed in retinaleading to rough-eye phenotype that forms a platform,which is used extensively for genetic and chemical screens

www.alzforum.org

www.alzforum.org


(Luheshi et al. 2007). The advantages working with fliesare short doubling time, multicellularity, availability ofgenetic resources and ability to express proteins in a tissue-specific manner. Also, the fly model can unravel the basicpathophysiological mechanisms underlying neurodegen-eration. It is often used synergisticallywith another diseasemodel to validate the basic mechanisms. For example, asmall molecule screen performed on fly model identifiedmGLUR5 (GPCR) as a druggable target that is abun-dantly expressed in brain (Chang et al. 2008). Recently,regulation of protein QPCT (glutaminyl cyclase) has beenshown to curb neurodegeneration symptoms in fly modeland mammalian cells (Jimenez-Sanchez et al. 2015).

Caenorhabditis elegans

It is one of the widely used models to study neurodegen-eration for more than a decade. Pros are the availability ofgenetic resources of this tiny transparent animal where all302 neurons are mapped for their interactions and theirshort generation time (Nussbaum-Krammer and Mori-moto 2014). Genetic strains were constructed that expresstoxic protein aggregates such as Aβ, α-synuclein, TDP43and polyglutamine repeats in either whole body or tis-sue specific manner. They not only form visible aggregatesbut also show the behaviour phenotype such as paralysis.Number of genetic and chemical screens was conductedto identify modulators that rescue the behavioural phe-notype. This led to identification of small molecules thatcleared toxic protein aggregates andwere further validatedin higher model systems (Narayan et al. 2014). Success-ful genetic screens too have identified many genes such asLRRK2, the reduction of its kinase activity rescued thedopaminergic deficit motor phenotype (Yao et al. 2013).Various regulators of HSR have been tested in the wormmodel to treat proteotoxicity. Its transparent tissue enablesfor high content imaging. More importantly, they alsoshow a typical ageing symptoms making them an idealtool to investigate the interplay of metabolism, ageing andneurodegeneration comprehensively (Chung et al. 2008).

Cellular models

Yeast

The budding yeast (Saccharomyces cerevisiae) is a simpleyet powerful tool to study the cellular pathophysiolog-ical mechanisms underlying the protein toxicity (Smithand Snyder 2006). It recapitulates the toxicity of proteinaggregates as that of neurons. This is because the funda-mental cellular features and vital cellular pathways areconserved (Khurana and Lindquist 2010). For instance,the membrane-bound organelles such as mitochondria,Golgi, lysosome, endoplasmic reticulum and so on existin yeast. More importantly, the unfolded protein response

is conserved as that of the mammalian cells. The majoradvantages of yeast are short doubling time, existence ofgenetic sources, amenable to genetic manipulation andscalable to high throughput genetic and chemical screens.Also, around 3500 genes are found to be homologues ofthose of human cells (Botstein et al. 1997; Kachroo et al.2015). Pioneering work by Susan Lindquist and her col-leagues have shown that yeast cells expressing aggregateprone genes and their variants that have been identifiedin ND have been used to understand their pathobiology(Outeiro and Lindquist 2003). The ER-Golgi traffick-ing defect due to α-synuclein overexpression leads tocellular toxicity was first noted in yeast and further val-idated in mammalian cells (Cooper et al. 2006; Winslowet al. 2010). Several studies including ours have identi-fied novel peptidomimetics and small molecule autophagymodulators that ameliorate ND related aggregate pro-teotoxicity (Sarkar et al. 2007b; Khurana and Lindquist2010; Rajasekhar et al. 2015). Some of the obvious limi-tation of the yeast model is that it cannot recapitulate thecomplexities of neuronal network andmulticellularity thatis present at the organ level.

iPSC

iPSC technology enables researchers to generate humanspecific, disease relevant cell type such as neurons directlyfrom patient fibroblasts. The advancement of gene editingtechniques such as CRISPR-Cas9 has simplified geneticknock out/in studies in iPSC-derived neurons to under-stand the pathogenesis of neurodegeneration. The poten-tial of this model system to shed light on basic diseasepathology mechanisms is massive (Narayan et al. 2014).iPSC lines for AD, PD, Niemann-Pick disease type Cand ALS disease have been generated for their biologicalinvestigations (Chung et al. 2013; Ryan et al. 2013; Kiski-nis et al. 2014). Consequently, genetic or small moleculescreens can be performed using iPSC. The current limi-tations are (i) hurdle in scaling up for high throughputscreening due to their relative slow propagation rates,(ii) extensive and time-consuming neuronal differentiationprotocols. However, they can be used to validate the datagenerated from nonhuman disease models. For example,yeast screen yielded theNAB2 compoundwhere it rescuedthe disease phenotype and validated its disease modifyingmechanisms in iPSC (Chung et al. 2013).

Current understanding on the mechanistic insights ofaggrephagy

These and the other model systems have contributedimmensely to unravel molecular aspects of the process ofaggrephagy. And how aggrephagy is perturbed by variousprotein aggregates is detailed below.


Substrate recognition

Protein aggregate (substrate) recognition by receptors/adaptors such as Alfy, p62/SQSTM1, Optineurin andCue5/Tollip, is one of the first steps of autophagy for itsclearance (Stolz et al. 2014). The selectivity of autophagiccargo depends on specific receptors/adaptors that recog-nize it by degradation marks. Autophagic receptors bindto the ubiquitinated substrates through their respectivedomains to capture the aggregates. They also tether themto autophagic machinery like LC3 to enable autophago-some formation around the aggregates. The brief descrip-tion pertaining to autophagic receptors are as follows:

Alfy : This multidomain scaffolding protein recognizesubiquitinated protein aggregates for their clearance. Itcontains followingdomains: (i) Pleckstrinhomology (PH)-BEACH domain that binds to p62, (ii) FYVE domainfor PI3P binding, and (iii) WD40 repeats that interactswithAtg5. It colocalizes with ubiquitin positive p62 aggre-gates (Isakson et al. 2013). It stabilizes the LC3 and p62interaction and also recruits Atg5 for the formation ofautophagosomes that facilitated huntingtin polyQ aggre-gate clearance (Filimonenko et al. 2010).

p62/SQSTM1 : p62 is the adaptor for aggrephagy (Pankivet al. 2007), mitophagy (Geisler et al. 2010), pexophagy(Kim et al. 2008b) and xenophagy (Bah and Vergne 2017).It possesses several domains namely: (i) UBA domainthat binds ubiquitin, (ii) PB1 domain for aggregation ofcargoes, and (iii) LC3 interacting region (LIR) motif forLC3 binding (Lim and Yue 2015). It also has nuclearlocalization signal (NLS) and nuclear export signal (NES)for nucleocytoplasmic shuttling (Pankiv et al. 2007). p62mutations have been linked to sporadic and familial ALSthrough impaired clearance of TDP-43 and SOD1 (Fectoet al. 2011). Paget’s disease of bone patientswithmutationsin p62 are predisposed to ALS, a disease that is character-ized by p62 positive inclusions in neurons. Mutant p62contributes to pathogenesis through multitude of mech-anisms and one of them is via over activation of nuclearfactor-κB (NF-κB) signalling (Chamoux et al. 2013).

Optineurin : It binds to ubiquitinated proteins through itsUBA and NF-kB essential modulator (NEMO) domains(Kachaner et al. 2012). On its other end, it binds toLC3 through LIR motif. Genetic mutations of optineurinare also associated with ALS. Optineurin mutation isassociatedwith rareALSmutations leading toTARDNA-binding protein 43 (TDP-43) inclusions (Ito et al. 2011).

Cue5 : Cue5 is the recently identified yeast autophagyreceptor that binds to ubiquitin through its CUE domainand Atg8 through its AIM1 and AIM2 motifs (Lu et al.2014). Its mammalian homologue is Tollip which is essen-tial for the huntingtin polyQ clearance.

Valosin-containing protein (VCP) : It is a member ofAAA+ family of ATPase and is involved in the sortingof ubiquitinated cargoes through endolysosomal path-way. VCP mutation is associated with Paget’s disease ofbone and fronto temporal dementia (FTD). Overexpres-sion or knockdown of VCP in cells leads to appearance ofautophagosomes that are immature with accumulation ofubiquitin positive cargoes (Ritz et al. 2011).

Autophagosome formation

mTOR complex 1 (TORC1) negatively regulates auto-phagy. Various stimuli in neurons such as ATP, ERstress, and specific amino acids repress TORC1 to acti-vate ULK complex (ULK1, FIP200, ULK2, Atg101 andAtg13) (Mizushima 2010). Phosphorylation of ULK1 atits active site leads to subsequent phosphorylation ofother components of complex for initiating autophagy(Chan et al. 2009). Although ULK1 phosphorylationis primarily regulated by TORC1, it can be also inde-pendently modulated by AMP-activated protein kinase(AMPK) (Khan and Kumar 2012). Also, ULK1 phos-phorylation leads to the translocation of class III PI3kinase complex (beclin1, Atg14, Vps15 and Vps34) to iso-lation membranes (also known as omegasome formationat the ER) by phosphorylating one of its components,AMBRA (Di Bartolomeo et al. 2010). Vps34 activity gen-erates phosphatidylinositol-3-phosphate (PI3P) to bind toits effectors such as WD repeat domain phosphoinositideinteracting 1 (WIPI1) and WD repeat domain phospho-inositide interacting 2 (WIPI2) (Jaber and Zong 2013).This is to catalyse the ubiquitination like reactions at theisolation membrane that aid autophagosome formation.Atg5–Atg12–Atg16L complex is formed on the isolationmembrane in presence of Atg7 and Atg10. This Atg5–Atg12–Atg16L catalyses the covalent attachment of phos-phatidylethanolamine to LC3 that facilitates the closure ofautophagosome membranes (Ichimura et al. 2000). Atg9aims to supply membranes for the growing autophago-somes by shuttling from various sources such as endo-plasmic reticulum-mitochondria contact sites (Hamasakiet al. 2013), Golgi (Geng and Klionsky 2010) and plasmamembrane (Ravikumar et al. 2010) to autophagosomeformation site. ER has been suggested as a membranesource for autophagosomes formed at synapse but themain source is not yet clear (Maday and Holzbaur 2014).In neurons, how autophagy induced is still an enigma.

Conventionally, the key trigger for autophagy is starva-tion that induces autophagy in numerous cell types (Kimet al. 2008a). However, even 48 h of starvation did notinduce GFP-LC3 puncta in brain but profoundly inducedautophagy in the liver (Mizushima et al. 2004). On theother hand, while caloric restriction induced autophagyin cortical, Purkinje and motor neurons, nutrient starva-tion failed to induce autophagy in cultured hippocampal


neurons (Kaushik et al. 2011). These contradicting resultsmay mirror the neuronal specificity in inducing and reg-ulating autophagy. Several studies have shed light about‘other’ ways of modulating autophagy in the brain.Recently, the neuronal activity such as acute stimuli

can trigger autophagy. Upon high frequency stimulation,the Atg8 puncta is increased at NMJ (presynapse) inD. melanogaster (Vanhauwaert et al. 2017). Although themolecular players and its mechanism(s) are not yet elu-cidated, calcium signalling can be a key player. Duringexocytosis driven by action potential, there is remarkableincrease in calcium levels at presynapse (Rizzoli 2014).Calcium can either enhance or inhibit autophagy depend-ing on the context and calcium responsive proteins areabundant at presynapse. It is noteworthy to mention thatinvestigating calcium-mediated autophagy at presynapsecan shed light on the novel mechanistic aspect of neuronalautophagy. Interestingly, the presynaptic resident proteinssuch as Endophilin A, Basoon, Synaptojanin 1 regulateautophagy by interacting with autophagy-related proteins(Vijayan and Verstreken 2017).Regulation of protein synthesis by TORC1 is impli-

cated in synaptic plasticity (Kovacs et al. 2007). However,TORC1-mediated autophagy induction at presynapse hasnot been studied extensively. Autophagy mediated degra-dation of GABA receptors and AMPA receptors (that areinvolved in synaptic plasticity) at postsynapse induce long-term depression (Shehata et al. 2012).

In PD model, α-synuclein perturbs Rab1a-mediatedAtg9 translocation to isolation membrane leading toimpairment of omegasome formation (Cooper et al. 2006).Atg9 trafficking is also abnormal in vacuolar proteinsorting-associated protein 35 (VPS35) D620N mutationthat results in autosomal dominant case of PD (Zhou et al.2017). VPS35 (component of retromer complex) recruitsactin nucleation-promoting WASP and Scar homologue(WASH) complex to endosomes. Mutation in VPS35perturbs this recruitment to cause the abnormal Atg9 traf-ficking to impair autophagy (Zavodszky et al. 2014). TheE122D Atg5 mutation has been identified in childhoodataxia (Kim et al. 2016). This disease is characterizedby loss of motor coordination and cerebellar hypoplasia.This mutation decreases the affinity of Atg5 to Atg12 andreduces the autophagosome biogenesis and its flux (Kimet al. 2016).

β-Propeller protein-associated neurodegeneration(BPAN), the static encephalopathy of childhood with neu-rodegeneration in adulthood (SENDA) is caused by denovo mutations in WDR45 (Haack et al. 2013). WDR45gene encodes WIPI4, the key protein that bridges PI3Pproduction and LC3 lipidation for autophagosome mat-uration (Zhao et al. 2015). Neuronal specific KO ofWDR45 recapitulates someBPANdisease phenotype suchas impaired motor coordination, cognitive deficit, axonalswelling with accumulation of ubiquitin positive aggre-gates (Saitsu et al. 2013).

Hexanucleotide repeats in C9ORF72 gene is one of themost common causes of ALS. Different mechanisms havebeen proposed for this disease pathogenesis and pertur-bation of autophagy is one of them. C9ORF72 interactswith ULK1 and affects the phagophore initiation com-plex (Webster et al. 2016). In addition, C9ORF72 is a partof WD repeat domain 41 (WDR41) and Smith–Magenissyndrome chromosome region, candidate 8 (SMCR8)complex that is involved in both vesicular traffickingand autophagy. This complex is a guanosine diphos-phate (GDP)/guanosine triphosphate (GTP) exchangefactor (GEF) that activates the small GTPases Rab39 andRab8 for autophagosome formation (Amick andFerguson2017).

Wild-type huntingtin protein acts as a scaffold forautophagosome formation whereas its mutant fails torecognize the cargo leading to ‘empty’ autophagosomes(Martinez-Vicente et al. 2010). It also impairs autophago-some transport and further accumulation of autophagicsubstrates (Wong andHolzbaur 2014).Mutant huntingtininteracts with Rhes that are selectively expressed in stria-tum to inactivate it. Rhes interacts with beclin 1 to induceautophagy by reducing the bcl2-beclin 1 interaction (Sub-ramaniam et al. 2009). Further,mTOR, is also sequesteredin HD and spino-cerebellar ataxia 7 (SCA7) aggregates(Jimenez-Sanchez et al. 2012).

Autophagosome–lysosome fusion

Autophagosomes fuse with lysosomes to generateautolysosomes that digest the toxic protein aggregates. Inneurons, autophagosomes generated in axons are trans-ported to the lysosomes that are abundant near perin-uclear microtubule-organizing centre (MTOC). Micro-tubules and motor proteins such as dynein–dynactincomplex are involved in retrograde transport ofautophagosomes towards neuronal cell body. Mutationsin dynein (axonal Charcot–Marie–Tooth hereditary neu-ropathy type 2) and dynactin (motor neuron disease)motor protein complexes are implicated in neurodegenera-tion pathogenesis indicating the importance of retrogradetransport of autophagosomes to fuse with lysosomes(Ferrucci et al. 2011). Interestingly, decreased dyneinactivity resulted in the accumulation of autophagosomes,autolysosomes and p62 positive inclusions in motor neu-rons before the onset of symptoms where they degenerateupon clinical manifestations (Sasaki 2011).Amphisome formation (a fusion product of endosomes

with autophagosome) is perturbed in familial ALS andFTD and is associated with loss-of-function mutationsin charged multivesicular body protein 2B (CHMP2B).Mutant CHMP2B neurons accumulate ubiquitinpositive inclusion by disrupting ESCRT machinery activ-ity (Skibinski et al. 2005). Autophagy and endolyso-somal pathways have significant crosstalk pertaining to


usage of cellular protein machineries. Mutations in anendolysosomal pathway affects autophagy and vice versa(Otomo et al. 2011). Endosomal maturation proteinRab7 is essential for autophagic flux and its mutationis associated with bone related osteopetrosis (lysosomalperturbation) and neurodegenerative CMT2 (autophagyflux perturbation) diseases (Tabata et al. 2010). Further,Rab7 significantly influences lysosome positioning. ALS2protein mutation, an activator of Rab5 perturbs ALS2mediated Rab5 activation that hampers amphisome for-mation as observed in familial cases of ALS (Otomo et al.2011). The coordinated crosstalk of endolysosomal andautophagy pathways to clear toxic protein aggregates inhealthy cells goes awry in neurodegeneration.In neuronal specific interferon-β KO of transgenic

mouse model, the autophagosome–lysosome fusion isaffected with concomitant accumulation of ubiquitin pos-itive inclusion in neurons that leads tomotor coordinationand behavioural impairments (Ejlerskov et al. 2015).

Regulation of lysosomal activity

Autophagosomes fuse with lysosomes for the clearance ofits contents. For this process to be efficient, the uncompro-mised lysosomal activity is essential. The lysosomal pH isoptimally (∼4.5–5) maintained by proton pump vacuolarATPase for the activity of hydrolytic enzymes (proteases,peptidases, lipases and nucleases). Ionic balances of lyso-somes are regulated by presence of numerous ion channels(calcium, chloride and potassium). Lysosomal associatedmembrane protein-1 (LAMP1) and LAMP2 prevents theself-digestion of lysosomes (Nixon 2013). The functionalintegrity of lysosomes is compromised in most neurode-generative disorders (Kroemer and Jaattela 2005).

Lysosomes serve as key players in the initial stage ofautophagy induction. Upon perceiving the autophagyinducing stimuli, the TORC1 localized on the lysosomalmembrane is repressed and that further allows activa-tion of transcription factor EB (TFEB) to translocate tothe nucleus. TFEB activates genes involved in lysosomalbiogenesis and autophagy process. TORC1 regulation ofTFEB is achieved through Rag-GTPase pathway (Kimet al. 2008a). TORC1 and TFEB activities are tightlycontrolled by the presence of intracellular and lysosomalamino acid contents. If amino acids are limiting inside thecells, for instance as in starvation, the TORC1 activityis repressed and is followed by translocation of dephos-phorylated TFEB to nucleus resulting in upregulation ofautophagy. On the other hand, the surplus amino acidslead to reactivation of TORC1 to terminate the autophagyinduction (Avruch et al. 2009). The androgen receptorpolyQ repeat mutant (implicated in SBMA) interacts withTFEB and suppresses autophagy at transcription level(Cortes et al. 2014). SCA3 transgenic animals show lowlevels of sirtuin 1 (deacetylates numerous autophagy and

its related proteins), parkin and beclin 1 (Cunha-Santoset al. 2016).Zinc-finger protein with KRAB and SCAN domains 3

(ZKSCAN3) is repressor of autophagy and has oppositefunction that of TFEB. Inhibition of mTOR enhances itsaccumulation in the cytosol. Downregulating ZKSCAN3induces autophagosome and lysosomal biogenesis(Chauhan et al. 2013). Apart from this, around 20 dif-ferent transcription factors are reported to regulate theautophagy at gene transcription level depending on thecontext of stimuli. For instance, p53, forkhead box O3(FOXO3) and microphthalmia-associated transcriptionfactor (MITF), all profoundly affect autophagy geneexpression (Li et al. 2017).

Lysosomal storage disorders (LSDs) illustrates thenexus between lysosomal dysfunction and neurodegener-ation. In LSDs, the unavailability of functional lysosomalhydrolytic enzymes leads to defective autophagy thatman-ifests disease pathology in brain. In Niemann Pick type C(NPC) disease, themutations ofNPC1 and/orNPC2 geneslead to defective cholesterol trafficking where profoundautophagic vacuole are observed in neurons (Elrick et al.2012). In neuronal ceroid lipofuscinosis, the mutation inCLN3 gene reduces autolysosome formation, whereas inCathepsin D mutation that causes the same disease wheredeclined lysosomal proteolysis is observed (Nixon 2004).

Therapeutic strategies for ND

Current therapeutic interventions for neurodegenerationinclude three different strategies. First, preventing thetoxic protein aggregate build-up. For instance, the anti-senseoligonucleotides ameliorated the amyotrophic lateralsclerosis disease phenotype under preclinical settings andshowed significant safety in phase I clinical trial (Niz-zardo et al. 2016). Second, dissolving the already culmi-nated toxic protein aggregates inside the neurons. Variousgroups identified small molecules and peptides that canbring about disintegration of the aggregate. This has beena widely used strategy for many years as a promisingantineurodegeneration therapeutic. For AD, few smallmolecule candidates that dissolve the amyloid plaques arecurrently in the clinical trials inUSAandEurope.The thirdand recent approach is to promote cellular pathways tocapture and degrade the protein aggregates by either ubiq-uitin proteasome (UPS) or autophagy systems. Numerousgroups have demonstrated that neurodegeneration couldbe ameliorated by upregulating the activities of cellu-lar clearance systems such as proteasome or autophagythrough smallmolecules or peptides.Many smallmoleculescreens have been reported that have identified the drug-gable candidate(s) (target proteins or pathways). Forexample, Rilmenidine, an autophagy inducer is currentlyin clinical trial as a HD therapeutic in Europe.


Chemical modulation of autophagy

As mentioned earlier that upregulation of autophagygene expression enhances the longevity of several modelorganisms (Pyo et al. 2013). Convincing evidences demon-strate that dysfunctional autophagy contribute to thepathogenesis of neurodegeneration (Nixon 2013). Impor-tantly, autophagy can clear the toxic misfolded proteinaggregates. Mechanisms that govern degradation of toxicmisfolded protein aggregates is thus a therapeuticallyattractive target (Sarkar et al. 2007b). Numerous stud-ies demonstrated that pharmacological upregulation ofautophagy to clear protein aggregates is beneficial in ame-liorating neurodegeneration.

mTOR dependent autophagy modulators

mTORdependentmodulators induce autophagy by repre-ssing mTOR and it can be of ATP competitive (e.g.,Torin1) or nonATP competitive (e.g., rapamycin). mTORcan be found in two complexes such as TORC1 (negativeregulator of autophagy) and TORC2 (positive regulator ofautophagy). Rapamycin and their analogues are relativelysafer owing to its nonATP competitivemode of inhibition.The allosteric TORC1 inhibitor, rapamycin was the firstidentified small molecule autophagy inducer. Rapamycininteracts with FK506-binding protein 12 (FKBP12) toinhibit the TORC1 activity (Lorenz and Heitman 1995).Rapamycin has been demonstrated to be neuroprotectivein various diseases such as PD, HD, AD and FTD inan autophagy dependent manner (Jahrling and Laberge2015). Limited absorption of rapamycin led to the devel-opment of its analogues (rapalogues) such as everolimus,temsirolimus, and ridaforolimus. Rapalogues are underrigorous investigation for their therapeutic potential inneurodegeneration. For instance, food and drug adminis-tration (FDA) approved everolimus as a tuberous sclerosistherapeutic (Bissler et al. 2017). Torin1 inhibits bothTORC1 and TORC2 in concentration dependent man-ner (Ma et al. 2013). There are classes of modulators thatindirectly inhibit mTOR activity. For instance, metformin(type II diabetes therapeutic) inhibits mTOR throughregulating AMPK pathway. Another AMPK activator,Nilotinib also exerts neuroprotection by inhibitingmTORactivity and is currently under phase II clinical trial for PDtherapy (Karuppagounder et al. 2014). PI103 belong todual mTOR/class III PI3Kinase modulators that inhibitboth mTOR and AKT pathway to induce autophagy.However, due to its rapid in vivometabolism, PI103 is cur-rently unsuitable for neurodegeneration therapy (Hassanet al. 2013).

mTOR independent autophagy modulators

mTOR independent autophagy modulators are thosethat induce autophagy without repressing the mTOR

activity. mTOR being the epicentre for cellular growthsignalling whose chronic inhibition exerts significant tox-icity. These inhibitors are preferred therapeutically assignificant side effects such as impaired wound healingand immunosuppression that are classically associatedwith mTOR inhibitors can be avoided. Thus, these arealso more suited for long-term drug administration. Smallmolecule screening for FDA approved drugs revealedthat several modulators ameliorated neurodegenerationpathogenesis in various model systems in mTOR inde-pendent manner. This study revealed the involvement oftwo cyclical pathways namely Gs α /calpain/Ca2+ (Car-denas et al. 2010) and EPAC/cAMP/PLC ε /Ins(1,4,5)P3(Williams et al. 2008) that are important for the mTORindependent clearance of aggregates.Rilmenidine, the imidazoline receptor inhibitor, enhan-

ces autophagy by reducing cAMP levels. It has been shownto ameliorate neurodegeneration in variousmodel systemssuch as primary neurons and transgenic mouse models ofHD. It is important to note that rilmenidine is currentlyundergoing safety trials for HD in Europe (Williams et al.2008).

Other drugs identified to regulate autophagy throughthe cyclical pathway are lithium, valproic acid and car-bamazepine. Carbamazepine and valproic acid repressinositol synthesis, while lithium inhibits inositolmonophosphatase to reduce Ins(1,4,5)P3 levels and thusinduce autophagy (Williams et al. 2008).

Modulators ofGs α /calpain/Ca2+pathway suchas vera-pamil and amiodarone along with calpain inhibitors suchas calpeptin and calpastatin have shown to exert neuro-protective potential by degrading the protein aggregatesthrough an autophagy-mediated mechanism (Williamset al. 2008).Trehalose clearsα-synuclein andmutant huntingtin pro-

tein aggregates in autophagy dependentmanner in variousmodel systems (Sarkar et al. 2007a). It has been shown tobe neuroprotective in tauopathy models as well (Schaefferet al. 2012). It extends life span, curbs motor and cognitivedeficits in transgenic HD andALSmousemodels (Tanakaet al. 2004).

Perspectives

The aetiological components, as well as the molecularand cellular points of convergence in ND, remain elu-sive and hence optimizing a defined therapeutic approachhas been challenging. Cellular mechanisms that directlyimpact synaptic function, including autophagy, endoso-mal trafficking, and mitochondrial homeostasis, are likelyto constitute effective interventional targets in therapy infuture. It is becoming increasingly evident from recent lit-erature that clearing protein aggregates through proteinquality control systems such as aggrephagy hold thera-peutic promise for curbing neurodegenerative diseases.


Acknowledgements

We thank members of the autophagy lab (JNCASR),Mridhula Giridharan and Aparna Hebbar for critical reading ofthe manuscript. We apologize to researchers whose work couldnot be included due to constraint in space. We acknowledgeWellcome Trust/DBT India Alliance Intermediate Fellowship(500159-Z-09-Z), DST-SERB Grant (EMR/2015/001946) andLSRB-DRDO Grant (LSRB-31012017-2018) to RM, DST-SERB Grant (EMR/2015/001946) to JC, and JNCASR intra-mural funds.

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