PINK1/PARKIN signalling in neurodegeneration and neuroinflammation

Quinne al. ac a neu opa hol commun (2020) 8:189 h ps://doi.o g/10.1186/s40478-020-01062-w REVIEW PINK1/PARKIN signalling inneu odegene a ion andneu oin lamma ion Pe e M. J. Quinn1,2, Paula I. Mo ei a3,4,5, An ónio F ancisco Amb ósio4,6,7,8 and C. Hen ique Al es4,6,7,8* Abs ac Mu a ions in he PTEN-induced kinase 1 (PINK1) and Pa kin RBR E3 ubiqui in-p o ein ligase (PARKIN) genes a e associ- a ed wi h amilial o ms o Pa kinson’s disease (PD). PINK1, a p o ein kinase, and PARKIN, an E3 ubiqui in ligase, con ol he speci ic elimina ion o dys unc ional o supe luous mi ochond ia, hus ine- uning mi ochond ial ne wo k and p ese ing ene gy me abolism. PINK1 egula es PARKIN ansloca ion in impai ed mi ochond ia and d i es hei emo al ia selec i e au ophagy, a p ocess known as mi ophagy. As knowledge ob ained using di e en PINK1 and PARKIN ansgenic animal models is being ga he ed, g owing e idence suppo s he con ibu ion o mi ophagy impai men o se e al human pa hologies, including PD and Alzheime ’s diseases (AD). The e o e, he apeu ic in e - en ions aiming o modula e PINK1/PARKIN signalling migh ha e he po en ial o ea hese diseases. In his e iew, we will s a by discussing how he in e play o PINK1 and PARKIN signalling helps media e mi ochond ial physiology. We will con inue by deba ing he ole o mi ochond ial dys unc ion in diso de s such as amyo ophic la e al scle osis, Alzheime ’s, Hun ing on’s and Pa kinson’s diseases, as well as eye diseases such as age- ela ed macula degene a ion and glaucoma, and he causa i e ac o s leading o PINK1/PARKIN-media ed neu odegene a ion and neu oin lam- ma ion. Finally, we will discuss PINK1/PARKIN gene augmen a ion possibili ies wi h a pa icula ocus on AD, PD and glaucoma. Keywo ds: PINK1, PARKIN, Mi ophagy, Neu odegene a ion, Alzheime ’s disease, Pa kinson’s disease © The Au ho (s) 2020. Open Access This a icle is licensed unde a C ea i e Commons A ibu ion 4.0 In e na ional License, which pe mi s use, sha ing, adap a ion, dis ibu ion and ep oduc ion in any medium o o ma , as long as you gi e app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e Commons licence, and indica e i changes we e made. The images o o he hi d pa y ma e ial in his a icle a e included in he a icle’s C ea i e Commons licence, unless indica ed o he wise in a c edi line o he ma e ial. I ma e ial is no included in he a icle’s C ea i e Commons licence and you in ended use is no pe mi ed by s a u o y egula ion o exceeds he pe mi ed use, you will need o ob ain pe mission di ec ly om he copy igh holde . To iew a copy o his licence, isi h p://c ea i eco mmons .o g/licen ses/by/4.0/. The C ea i e Commons Public Domain Dedica ion wai e (h p://c ea i eco mmons .o g/publi cdoma in/ze o/1.0/) applies o he da a made a ailable in his a icle, unless o he wise s a ed in a c edi line o he da a. Backg ound Mi ochond ia, i s disco e ed in he la e 19 h cen u y, a e conside ed key o cellula bioene ge ics [1, 2]. They consis o a double memb ane wi h an in e memb ane space. The inne memb ane o ms olds called c is ae which p o ide an inc eased su ace a ea o chemical and edox eac ions o ake place [3–5]. Mi ochond ia p oduce he majo i y o cellula adenosine iphospha e (ATP) h ough oxida i e phospho yla ion (OXPHOS). The p o ein complexes (cI-IV) o he espi a o y chain ans e elec ons om NADH and FADH2 (p o ided by he K ebs cycle) o molecula O2, a p ocess also known as he elec on anspo chain (ETC). The ETC c ea es a memb ane po en ial (ΔΨm) ac oss he mi ochond ial inne memb ane by pumping p o ons om he mi o- chond ial ma ix o he in e memb ane space, hus c ea - ing a high concen a ion o p o ons in he in e memb ane space and a low concen a ion in he mi ochond ial ma ix. Subsequen ly, along his chemiosmo ic g adien , he p o ons mo e back in o he mi ochond ial ma ix, ia ATP syn hase (cV). ATP syn hase uses his p ocess o c ea e ATP om adenosine diphospha e (ADP) and ino - ganic phospha e (Pi) [6–9]. P e iously hough o be only he “powe house” o he cell i is now clea ha mi ochond ia a e mul i ace ed. In addi ion o hei ole in cellula bioene ge ics, mi o- chond ia con ol eac i e oxygen species (ROS) le els and calcium homeos asis, and biosyn hesize mac omol- ecules including lipids, amino acids and nucleo ides [10]. Fu he mo e, mi ochond ia a e in ol ed in many cellula Open Access *Co espondence: chal es@ med.uc.p 6 Coimb a Ins i u e o Clinical and Biomedical Resea ch (iCBR), Facul y o Medicine, Uni e si y o Coimb a, Coimb a, Po ugal Full lis o au ho in o ma ion is a ailable a he end o he a icle Page 2 o 20 Quinne al. ac a neu opa hol commun (2020) 8:189 physiological p ocesses, including cell a e, di e en ia- ion, p oli e a ion and apop osis [11, 12]. Alongside i s mo e es ablished oles, mi ochond ia a e key egula o s o he inna e and adap i e immune sys em. Immune cells unde go signi ican cell- ype speci ic me abolic changes du ing an immune esponse, mo ing om a quiescen o an ac i e s a e ha equi es signi ican me aboli es om mi ochond ia [13, 14]. Mi ochond ia can egula e immu- ni y ia me abolic pa hways, inducing ansc ip ional changes, ac i a ing in lamma ion, mi ochond ial dynam- ics ( ission and usion) and endoplasmic e iculum sig- nalling [14, 15]. Mi ochond ial s ess, ei he d i en by he en i on- men , pa hogenesis o ageing, leads o a my iad o dys- egula ion ha can cause bo h neu odegene a ion and neu oin lamma ion. Mi ochond ia a e i al in egula ing cellula adap ion o s esso s, including impai ed bio- genesis, mi ochond ial DNA (m DNA) damage, ageing, nu ien es ic ion and abe an imbalances be ween is- sion and usion e en s. I le unchecked, hese p ocesses can cause damage o nucleic acids, lipids and p o eins h ough ROS, esul ing in sus ained oxida i e s ess [16, 17]. Oxida i e s ess modula es mi ochond ial dynam- ics h ough pos ansc ip ional modi ica ions, including ubiqui ina ion [18]. This, in u n, leads o a build-up o damaged mi ochond ia and ul ima ely causes cell dea h and b oade issue dys unc ion. In pa icula , issues wi h high ene gy demands such as he hea , muscles, b ain and e ina a e suscep ible o mi ochond ial dys unc ion [19]. To mi iga e he e ec s o s esso s, se e al con ol mechanisms can be ac i a ed con ibu ing o mi ochon- d ial homeos asis [17]. Mi ochond ia i s -line de ence mechanisms includ- ing enzyma ic (such as supe oxide dismu ase, he pe - oxi edoxin/ hio edoxin sys em and he glu a hione pe oxidase/ educ ase sys em) and non-enzyma ic (such as GSH, i amins E, A and C) an ioxidan s con ibu e o he main enance o edox homeos asis [20]. Howe e , beyond he u iliza ion o an ioxidan s he e exis s se e al mi ochond ial quali y con ol mechanisms. These include egula ion o mi ochond ial ission and usion e en s, which acili a e seg ega ion o damaged mi ochond ia and axonal anspo o mi ochond ia ( ission) and he exchange o ma e ials needed o hei epai , such as m DNA ( usion) [16, 21]. The mi ochond ial un olded p o ein esponse sys em, a mi ochond ia- o-nucleus ansduc ion pa hway, which p omo es mi ochond ial and cellula unc ion i mi ochond ial damage is sensed [22]. The ubiqui in–p o easome sys em leads o deg ada- ion o damaged ou e mi ochond ial memb ane (OMM) p o eins, and p o eases lead o he emo al o inne mi o- chond ial memb ane (IMM) and mi ochond ial ma ix p o eins [23]. Las ly, he expo o damaged p o eins ia mi ochond ial-de i ed esicles (MDVs) o selec i e emo al o damaged mi ochond ia ia mi ophagy end wi h hei deg ada ion in lysosomes [24]. PTEN-induced kinase 1 (PINK1) and Pa kin RBR E3 ubiqui in-p o ein ligase (PARKIN) signalling play a key ole in mi ophagy and mi ochond ial mo ili y and size. PINK1 accumula es a he OMM in esponse o a educ- ion in mi ochond ial ΔΨm caused by damage/dys unc- ion. In u n, his ec ui s PARKIN om he cy osol o he OMM we e i s E3 ac i i y p omo es mi ophagy, h ough ubiqui ina ion o mi ochond ial p o eins, lead- ing o mi ochond ial deg ada ion. De ec i e mi ophagy and PINK1/PARKIN signalling a e p esen in neu ode- gene a i e diseases including Alzheime ’s disease (AD), Pa kinson’s disease (PD) and glaucoma [25–30]. Mu a ions in he PINK1/PARKIN signalling pa h- way dis up s he sensi i e homeos a ic and quali y con- ol p ocesses conduc ed by mi ochond ia. Mu a ions in PINK1 and PARKIN a e localised h oughou hei genes a ec ing all hei p o ein domains (Fig.1). PINK1 and PARKIN mu a ions a e esponsible o mo e han 50% o he au osomal ecessi e ju enile pa kinsonism (ARJP) cases [31]. Howe e , he e a e se e al o he caus- a i e genes o PD linked o mi ochond ial dys egula ion, including LRRK2, DJ1, ATP13A2 and SCNA, in addi ion o o he PD isk genes [32–45]. Fu he mo e, dys egula- ion o PINK1/PARKIN signalling has been associa ed wi h amyo ophic la e al scle osis (ALS) and Hun ing- on’s disease (HD), as well as eye diseases, such as age- ela ed macula degene a ion (AMD), and is associa ed wi h e inal degene a ion [46–51]. E o s o he ame- lio a ion o mi ochond ial dys unc ion h ough len i i al and adeno-associa ed i al (AAV) media ed PINK1 and PARKIN gene augmen a ion he apeu ics show p omise (Table1). Main ex PINK1/PARKIN signalling The mi ochond ial se ine/ h eonine-p o ein kinase PINK1, also known as BRPK and PARK6, p o ec s cells om mi ochond ial s ess-induced dys unc ion. Local- ized o ch omosome 1 in posi ion 1p36.12, he PINK1 gene has 8 exons encoding a 581 amino acid p o- ein. I con ains an N- e minal mi ochond ial a ge - ing sequence (MTS), a ansmemb ane domain (TM), a N- e minal egula o y domain (NT), a conse ed p o ein kinase domain comp ising o a N-lobe and C-lobe, and las ly a C- e minal domain (CTD) (Fig.1a). PARKIN, also known as PDJ, AR-JP, LPRS2 and PARK2 is localized o ch omosome 6 in posi ion 6q26 [61, 62]. PARKIN gene has 14 exons encoding a 465 amino acid p o ein which is comp ised o an N- e minal ubiqui in-like (Ubl) domain and a C- e minal RING1-IBR-RING2 (RBR) domain. Page 3 o 20 Quinne al. ac a neu opa hol commun (2020) 8:189 A RING0 domain si s N- e minally adjacen o RING1 and esiding be ween he in-be ween-RING (IBR), and RING2 domains is a Rep esso Elemen o Pa kin (REP) mo i (Fig.1b) [63–66]. Unde heal hy condi ions, mi o- chond ia ha e an op imal, ela i ely high ΔΨm and will impo , p ocess and lead o he deg ada ion o PINK1 (Fig.2). Howe e , unde unheal hy condi ions like oxi- da i e s ess, low ΔΨm causes PINK1 mi ochond ial accumula ion leading o PARKIN ec ui men om he cy oplasm and ini ia ion o au ophagic deg ada ion o he damaged mi ochond ia, he mi ophagy pa hway (Fig.3) [67–70]. This pa hway is go e ned by phospho yla ion and ubiqui ina ion, pos ansc ip ional modi ica ions media ed by PINK1 and PARKIN, espec i ely. The igh ly egula ed impo o and subsequen p o e- olysis o PINK1 in he mi ochond ia leads o i s p ocess- ing om he ull leng h 63kDa p o ein p ecu so o he mi ochond ial p ocessing pep idase (MPP)-p ocessed 60 kDa in e media ed, o i s inal p esenilins-associ- a ed homboid-like p o ein (PARL)-p ocessed 52 kDa “ma u e” o m (Fig. 2a, b) [71–73]. The anslocase o he ou e memb ane (TOM) and o he inne memb ane Fig. 1 Schema ic ep esen a ions o PINK1 and PARKIN domains and disease- ela ed mu a ions. a PINK1 is composed by 581 amino acids, encompassing he mi ochond ial a ge ing sequence (MTS), ansmemb ane egion (TM), N- e minal egula o y egion (NT), N-lobe o he kinase domain, C-lobe o he kinase domain and he C- e minal domain (CTD). Mi ochond ial p ocessing pep idase (MPP) and p esenilin-associa ed homboid-like (PARL) clea age si es and PINK1 au o-phospho yla ion si es a e depic ed in he igu e (S228, T257, S402). b PARKIN is o med by 465 amino acids wi h a ubiqui in-like domain (UBL), linke , eally-in e es ing-new-gene (RING)/unique Pa kin domain (R0/UPD), RING1 (R1), in-be ween-RING (IBR), ep esso elemen o Pa kin (REP), and a RING2 (R2) domain. E2 co-enzyme and p-Se 65-Ub binding si es, as well as Se 65 phospho yla ion and Cys431 ca aly ic si es, a e displayed. Disease-associa ed mu a ions collec ed om he mo emen diso de socie y gene ic mu a ion (www.mdsge ne.o g/) and ClinVAR (www.ncbi.nlm.nih.go /clin a /) da abases a e displayed on op o schema ic ep esen a ion. In ed a e depic ed he mu a ions conside ed pa hogenic Page 4 o 20 Quinne al. ac a neu opa hol commun (2020) 8:189 (TIM)23 complexes acili a e he impo a ion o he PINK1 p ecu so ia in e ac ion wi h i s MTS o he IMM. A he IMM, PINK1 unde goes clea age a Ala103 by he p o ease PARL in a ΔΨm dependen manne . Unde no mal, heal hy condi ions PINK1 is impo ed and p ocessed o deg ada ion. In con as , i ΔΨm dis- sipa es, PINK1 emains localized o he OMM and is unable o be p ocessed by PARL [72, 74]. Upon clea age, PINK1 e u ns o he cy osol o be deg aded by he ubiq- ui in–p o easome sys em by UBR1, UBR2 and UBR4 h ough he N-end ule pa hway, leading o low le els o PINK1 (Fig.2a, b) [75]. Recen ly Sekine e al. [76] ound some PD ela ed PINK1 mu a ions, I111S, C125G and Q126P, a ec ing an e olu iona y conse ed nega i ely cha ged amino acid clus e mo i ha cons i u es he C- e minal o he PINK1 TM, can s ill be impo ed e en Table 1 Summa y o  hePARKIN andPINK1 gene augmen a ion i al ec o s AAV Adeno-associa ed i us, CBA hyb id cy omegalo i us immedia e/ea ly enhance -chicken β-ac in, CMV cy omegalo i us, PGK phosphoglyce a e kinase, S.N. subs an ia nig a, TU ansducing uni s, Vg i al genomes, VSVG esicula s oma i is i us Vi uses Capsid se o ype P omo e Sequence Injec ion place Volume injec ed Dose Disease model Animal Re e ences Len i i us HIV-1 based ec o wi h VSVG en elops PGK Ra Pa kin S.N. 2.5 µl 3.6 × 108 pg o p24 pe ml α-synuclein a model o PD Wis a a s [52] Len i i us HIV-1 based ec o wi h VSVG en elops CMV Human PARKIN S.N. 2 µl 108 pg o p24 pe ml 6-Hyd oxy- dopamine a model o PD Ra s [53] AAV 2/2 CBA HA- agged- PARKIN S.N. 2 µl 3.6 × 1012 g/ ml MPTP- ea ed mice, a model o spo adic PD C57BL/6 mice [54] AAV 2/2 and 2/5 CMV/CBA Human PARKIN S.N. 2 × 2 µl 2.6 × 1012 g/ ml 6-Hyd oxy- dopamine a model o PD Ra s [55] AAV 2/2 CMV/CBA Human PARKIN S.N. 4 µl 5 × 1012 g/ml Tau-induced dopamin- e gic degen- e a ion a model o PD Sp ague– Dawley a s [56] AAV 2/6 PGK Ra Pa kin S.N. 2 µl 4.7 × 1010 TUs/ml Me ham- phe amine induced neu o oxic- i y a model o PD Sp ague– Dawley a s [57] AAV 2/8 CMV Human PARKIN S.N. 2 µl in mice 3 µl in a s 2.0 × 1011 g/ ml T240R-PARKIN induced dopa- mine gic degene a- ion model o PD C57BL/6 J mice Wis a a s [58] AAV 2/2 CMV Ra Pa kin Vi eous 5 µl 1.0 × 1013 g/ ml Ch onic hype - ensi e glaucoma model Sp ague– Dawley a s [30] AAV 2/1 CMV Human PARKIN S ia um 3 µl in a s 5 × 10 µl in monkeys 7.0 × 1012 g/ ml α-synuclein a model o PD Sp ague– Dawley a s Macaque monkeys [59] AAV 2/2 CMV Human PINK1 Hippocampus 2 µl 5.0 × 1012 g/ ml mAPP mouse model o AD mice [60] Page 5 o 20 Quinne al. ac a neu opa hol commun (2020) 8:189 i ΔΨm dissipa es. These mu an s we e ound no o be clea ed by PARL bu by he p o ease OMA1 a he IMM, sugges ing ha PINK1 did no accumula e on he dam- aged mi ochond ia’s OMM o ini ia ion o mi ophagy. Howe e , hese PINK1 mu an s could lead o PARKIN ec ui men unde OMA1 supp ession. In con adic ion o he deg ada ion o he 52 kDa PINK1 by he N-end ule pa hway is he inding by he P zedbo ski Lab ha ubiqui ina ed PINK1 is mos ly ancho ed o he OMM and no in he cy osol. Impo - an ly, hey iden i ied ha he N- e minal phenylalanine o ming a p oposed N-deg on mo i o PINK1 was no acing he cy osol bu a he loca ed inside he OMM, sugges ing PINK1’s low mi ochond ial le els a e due o con inuous ubiqui ina ion and p o easomal deg ada ion unde heal hy condi ions [73]. Recen ly, he same eam iden i ied he mechanism by which PINK1 con en is kep a low le els. They ound ha upon PARL-p ocess- ing he 52kDa PINK1 localizes a he mi ochond ial- endoplasmic e iculum in e ace and can in e ac wi h ER-associa ed deg ada ion pa hway E3 ligases Gp78 and HRD1 (Fig.2c). These acili a e PINK1’s ubiqui ina ion allowing alosin con aining p o eins, UFD1 and UFD2A, o a ge PINK1 o p o easomal deg ada ion [77]. O he p o eases such as ma ix-AAA and caseinoly ic mi o- chond ial ma ix pep idase (ClpXP) can clea e PINK1. These may coo dina e wi h PARL o go e n he s abili y and localiza ion o PINK1 [71, 75]. In damaged mi o- chond ia, TOM does no impo PINK1, and i emains unclea ed a he OMM, whe e i unde goes dime iza ion and au ophospho yla ion (Fig.3) [78, 79]. In e es ingly, Sekine e al. [76] ound ha wi hou he TOM complex Fig. 2 The canonical PINK1/PARKIN pa hway. a and b In heal hy mi ochond ia, PINK1 is cons i u i ely impo ed ia anslocase o he ou e memb ane (TOM)/ anslocase o he inne memb ane (TIM)23 complexes o he inne mi ochond ial memb ane (IMM), clea ed by wo p o eases (mi ochond ial p ocessing pep idase (MPP) and p esenilin-associa ed homboid-like (PARL)) and e o- ansloca ed o he cy osol. Clea ed PINK1 is hen deg aded by he ubiqui in/p o easome sys em. While Pa kin emains inac i e in he cy osol. (a and c) PINK1 is also p esen a he mi ochond ia-endoplasmic e iculum (ER) in e ace, whe e i in e ac s wi h he endoplasmic- e iculum-associa ed p o ein deg ada ion (ERAD) machine y. A he ER, PINK1 deg ada ion by he p o easome is con olled by he ERAD E3 ubiqui in ligases HRD1 and gp78 and by he ERAD-associa ed p o eins VCP, UFD1, andUFD2A Page 6 o 20 Quinne al. ac a neu opa hol commun (2020) 8:189 accesso y membe Tom7 PINK1 was impo ed o depo- la ised mi ochond ia. Tom7 appea s c ucial in PINK1 OMM accumula ion and also plays a ole in PINK1 kinase ac i a ion o PARKIN ec ui men . Phospho- glyce a e mu ase amily membe 5 (PGAM5) also binds PINK1 and is equi ed o mi ochond ial s abilisa ion o ull-leng h PINK1 on he OMM upon mi ochond ial depola isa ion, p e en ing i s clea age by PARL a he IMM [80]. Unde basal condi ions, h ee ac o s ha e been iden- i ied which show ha PARKIN’s p o ein- olding main- ains PARKIN in an au oinhibi ed s a e: (1) inaccessibili y o he E2-binding si e on RING1 due o i s occlusion by he REP domain [65]; (2) a conse ed cys eine esidue on RING2 (Cys431) is made inaccessible by RING0 [64, 65, 81]; (3) he Ubl domain inhibi s pa kin ac i i y h ough he in e ace wi h RING1 and IBR domains [82–85]. The p o ein olding o PARKIN hus p e en s he binding o Ub con aining E2s o RING1 and he subsequen hiol- based ans e o Ub o he RING2 cys eine esidue. The Cys431 esidue is ca aly ic, being equi ed o he ligase ac i i y o PARKIN. The ca aly ic esidue allows o he o ma ion o an isopep ide bond be ween Ub and he lysine esidue o he p o ein [64, 65, 86]. PINK1 is ups eam o PARKIN and h ough he Ub/ Ubl swi ch leads o ac i a ion o PARKIN by hei phos- pho yla ion a esidue Se 65 (Fig.3) [83, 84, 87–93]. Phos- pho yla ion o Ubl inc eases PARKIN’s a ini y o pUb. The binding o pUb o PARKIN enhances he a e a which PARKIN i sel is phospho yla ed by PINK1 [94, 95]. Spe- ci ic phospho yla ion o ei he Ub o Ubl leads o PARKIN ac i a ion; concomi an phospho yla ion, howe e , leads o enhanced PARKIN ac i a ion [91, 92, 94]. Binding o pUb o PARKIN’s Ubl domain is essen ial o emodel- ling o and exposu e o RING1 o he binding o he Ub con aining E2s and is in line wi h p e ious compu a ional analysis [83, 96, 97]. Ubl phospho yla ion o binding o pUb o Ubl has also been shown o lead o local ea - angemen o he IBR and i s dec eased a ini y o he Ubl domain, e ealing c yp ic binding si es in a egion called he Ubiqui in Binding Region (UBR) [85]. Th ee su ace a eas, UBR1, 2 and 3, ha could in e ac wi h Ub we e explo ed. Bo h UBR2 and UBR3 we e needed o PARKIN ac i i y. The IBR ea angemen in ac i e PARKIN allows binding o Ub con aining E2s o he binding si e on RING1 while i s Ub c ea es a b idge o he IBR o a neighbou ing PARKIN molecule [85]. This associa ion allows o he u i- liza ion o he RING2 ca aly ic domain o neighbou ing PARKIN molecules [85]. In summa y, pUb is impo an o dissocia ion and phospho yla ion o PARKIN’s Ubl domain allowing i s ec ui men o he mi ochond ia. Sub- sequen PINK1 ac i a ion o PARKIN h ough Se 65 phos- pho yla ion in he Ubl acili a es binding o E2 enzymes leading o PARKIN’s ligase ac i i y. Se e al mu a ions exis h oughou PARKIN, a ec ing i s ac i i y and s abili y (Fig.1b) [98–100]. I he e is se e e mi ochond ial dys unc ion he ampli- ied phospho-ubiqui in chains on he OMM signal he ec ui men o au ophagy adap o s such as nuclea do Fig. 3 PINK1/PARKIN-di ec ed quali y con ol in damaged mi ochond ia. A e damage, PINK1 is no longe impo ed in o he inne mi ochond ial memb ane (IMM) and accumula es on he ou e mi ochond ial memb ane (OMM). He e, a supe complex composed by TOM complex subuni s and PINK1 homodime s is o med, acili a ing PINK1 au ophospho yla ion and ac i a ion. Once ac i a ed, PINK1 phospho yla es ubiqui ina ed subs a es on he OMM and PARKIN enable i s E3 ubiqui in ligase unc ions in conce wi h E2 ubiqui in-conjuga ing enzymes. PINK1-media ed phospho yla ion o ubiqui in phospho-Se 65- ubiqui in on OMM subs a es ac s as he PARKIN ecep o o i s ec ui men om he cy osol. PINK1 and PARKIN ini ia e a posi i e eedback loop, esul ing in he coa ing o damaged mi ochond ia wi h phospho-ubiqui in chains. Indi idual OMM p o eins deco a ed wi h poly-ubiqui in can be ex ac ed om he memb ane and deg aded by he 26 S p o easome. Phospho-ubiqui in chains a e bound by wo mi ophagy adap o s, nuclea domain 10 p o ein 52 (NDP52) and op ineu in. Phospho yla ion o op ineu in by TANK Binding Kinase 1 (TBK1) enhances i s binding o ubiqui in chains and p omo es selec i e au ophagy o damaged mi ochond ia. The wo adap o s ec ui au ophagosomes ia mic o ubule-associa ed p o ein 1A/1B-ligh chain 3 (LC3) binding, allowing he engul men o dys unc ional mi ochond ia esul ing in hei di ec deg ada ion in lysosome Page 7 o 20 Quinne al. ac a neu opa hol commun (2020) 8:189 p o ein 52 (NDP52) and Op ineu in (OPTN). In u n, NDP52 and OPTN lead o he ec ui men and ac i a- ion o ank binding kinase 1 (TBK1), ac i a ed TBK1 phospho yla es OPTN s abilizing i s binding a he phospho-ubiqui in chains [101]. In e es ingly, PINK1/ PARKIN-dependen mi ophagy-induced seques a- ion o TBK1 leads o i s emo al om i s physiological ole a he cen osome causing G2/M cell cycle a es . This highligh s a possible ole o PINK1/PARKINs in mi ochond ial quali y con ol be o e cell di ision akes place, p e en ing “un i ” mi ochond ia being passed on o daugh e cells [102]. OPTN and NDP52 along wi h o he au ophagy adap o s lead o he ec ui men o mic o ubule-associa ed p o eins 1A/1B ligh chain 3 (LC3), which engage wi h he au ophagosome. Mig a- ion and subsequen usion o he au ophagosome wi h he lysosome, which is modula ed by he RAS- ela ed GTP-binding (Rab) p o eins, c ea es he au olysosome whe e he mi ochond ial p o eins a e deg aded and p ocessed o ecycling (Fig.3). Ini ia ion o au ophagy has been ound in he absence o LC3 ia he Unc-51 like kinase 1 (ULK1) complex, which is comp ised o ULK1, FAK amily kinase-in e ac ing p o ein o 200kDa (FIP200), au ophagy ela ed gene (ATG)12 and ATG101 [103]. The ULK1 complex, which media es au ophagy in a nu ien -dependen manne , is ec ui ed o ubiqui- na ed ca go independen ly o AMPK by he coope a ion o NDP52, and TBK1 [103]. Recen ly, Nozawa e al. [104] ound ha TBC1 domain amily membe 9 (TBC1D9), which is ec ui ed o mi ochond ia ia Ca2+-dependen Ub-binding, is essen ial o he ac i a ion and ec ui - men o TBK1 and he e o e he subsequen ec ui - men o NDP52 and he ULK1 complex o damaged mi ochond ia. PINK1/PARKIN inneu odegene a ion Neu odegene a ion co esponds o any pa hological condi ions, p ima ily a ec ing neu ons [105]. Typically, neu odegene a i e diseases a e p og essi e diso de s ha lead o neu onal degene a ion and cell dea h. The umb ella e m “neu odegene a i e diseases” includes condi ions such as AD, PD, amyo ophic la e al scle o- sis (ALS), Hun ing on’s disease (HD) and also eye dis- eases, such as age- ela ed macula degene a ion (AMD), glaucoma and a subse o inhe i ed e inal dys ophies. Ageing is conside ed a p ima y isk ac o in mos neu o- degene a i e diseases [106]. Mi ophagy inc eases in mus- cles and neu ons du ing ageing bu dis up ion o PINK1/ PARKIN signalling abolishes his inc ease, hinde ing his c ucial quali y con ol mechanism and hus allow- ing he accumula ion o ha m ul mi ochond ia [107– 111]. Imbalances in mi ochond ial ission and usion a e impo an o neu onal dynamics and a e a ec ed in neu odegene a ion being linked o p og ammed cell dea h pa hways [112]. PINK1 and PARKIN a e essen ial in hese p ocesses in e ac ing wi h ission/ usion machin- e y molecules such as ission p o ein D p1 (dynamin- ela ed p o ein 1) and usion p o ein OPA1 (op ical a ophy 1). O e exp ession o Pink1 o Pa kin in a hip- pocampal neu ons leads o inc eased ission and can sup- p ess a mi ochond ial elonga ion pheno ype caused by D p1 knockdown. A simila pheno ype is caused by PINK1 inac i a ion, leading o inc eased usion. Yu e al. [113] ound ha in dopamine gic neu ons, simila ly o hippocampal neu ons, PINK1/PARKIN had a compa a- ble in luence on mi ochond ial dynamics wi h ipping he ission/ usion balance owa ds mo e ission. Alzheime ’s disease, he mos common cause o demen ia in he elde ly, is a p og essi e neu odegen- e a i e disease leading o memo y de ici s and cogni i e decline, which in u n lead o beha iou al and speech impai men s. Ageing is he p edominan isk ac o wi h a p e alence o 10% o indi iduals o e he age o 65 [114]. Pa hologically, AD is hallma ked by he p es- ence o amyloid plaques, mainly consis ing o agglome - a ed amyloid-β (Aβ) pep ides, and neu o ib illa y angles, mos ly consis ing o hype phospho yla ed au, which a e associa ed o cellula degene a ion [115]. Ano he p ominen hallma k o AD is he accumula ion o dys- unc ional mi ochond ia [116]. Robus induc ion o PAR- KIN-media ed mi ophagy is ound in human pa ien s’ b ains and in a human amyloid p ecu so p o ein (hAPP) ansgenic mouse model o AD [28]. Du ing disease p o- g ession, cy osolic PARKIN le els a e educed, leading o inc eased mi ochond ial dys unc ion [28]. Mi ochond ia om AD pa ien s skin ib oblas s exhibi ed slowe eco - e y o ΔΨm a e insul [27]. Dys egula ed p o ein le els o PARKIN and PINK1 we e ound in AD ib oblas s and b ain biopsies. In bo h AD ib oblas s and hippocampal b ain biopsies om B aak II-III s age pa ien s, ull leng h and clea ed PINK1 we e inc eased. Howe e , while PARKIN was diminished in he AD ib oblas s, i was ound up egula ed in B aak VI s age hippocampal b ain biopsies. In AD ib oblas s, PARKIN ec ui men a e mi ochond ia depola isa ion was ound o be educed, indica ing de ec i e mi ophagy due o insu icien agging o damaged mi ochond ia. O e exp ession o PARKIN could compensa e o he de ec i e mi ophagy in he AD ib oblas s [27]. Familial cases o AD a e linked o au o- somal dominan mu a ions o p esenilin 1 (PSEN1). Bo h PSEN1 and PSEN2 a e in ol ed in a molecula cascade ha modula es mi ophagy ia hei con ol o PINK1 ansc ip ion and unc ion. Goi an e al. ound ha PAR- KIN up egula es PSEN1 p omo e ac i a ion. In u n, con ol o γ-sec e ase ac i i y, by PSEN1, a ge s APP leading o i s agmen a ion, yielding Aβ and he APP Page 8 o 20 Quinne al. ac a neu opa hol commun (2020) 8:189 in acellula domain (AICD). In e ac ion o o khead box O3a (FOXO3a) wi h AICD ini ia es Pink1 ansc ip ion and AICD-media ed con ol o au ophagic p ocesses, which we e ound o be PINK1 dependen . As PINK1 ec ui s PARKIN o damaged mi ochond ia his high- ligh s a eedback loop be ween he wo genes ha may become dis up ed in neu odegene a i e condi ions [117, 118]. Pa kinson’s disease is a mo emen diso de a ibu ed o he loss o dopamine gic neu ons in he subs an ia nig a. Mo o symp oms include es ing emo , igidi y and b adykinesias, while non-mo o symp oms include au onomic dys unc ion, anxie y and sleeping p oblems. PINK1 and PARKIN a e mu a ed in some o ms o amil- ial PD [119, 120]. Pink1 and Pa kin null D osophila ha e lea ning and memo y abno mali ies and weakened ci - cadian hy hms, in addi ion o unde lying elec ophysi- ological i egula i ies in clock neu ons [121]. La e-s age PD pa ien s can de elop demen ia wi h an accumula ion o α-synuclein in Lewy bodies [41, 59, 122, 123]. Ni o- sa i e s ess is a key pa hological hallma k in PD and aging. Ni ic oxide-induced S-ni osyla ion o PARKIN and PINK1 leads o comp omised mi ophagy and hus accumula ion o damaged mi ochond ia [124–126]. One o he majo causes o ea ly-onse PD is due o loss-o - unc ion mu a ions in genes including glucoce eb o- sidase (GBA), RAB39B, DJ-1, PINK1 and PARKIN [25, 26, 127–130]. Pink1 and Pa kin KO mice show minimal signs o neu odegene a ion bu s ill p o ide aluable insigh s in o possible mechanisms o ac ion [131–135]. Pa kin KO mice ha e an inc ease in ex acellula dopa- mine concen a ion in he s ia um, he e is educ ion in synap ic exci abili y in spiny neu ons and dys unc ion o he nig os ia al pa hway [131]. Ano he mouse model, p esen ing inac i a ed PARKIN due o a exon 3 dele- ion causing a p ema u e s op codon, showed cogni i e and mo o de ici s wi h inhibi ion o bo h amphe amine- induced dopamine elease and glu ama e neu o ans- mission [133]. Addi ionally, some mouse and a Pa kin KO models exhibi no neu odegene a ion o any de ec - able neu ochemical o pa hological changes compa ed o wild ype coun e pa s [135, 136]. This may be due o de elopmen al compensa ion o PARKIN in hese models. Due o he lack o neu odegene a ion ound in mouse KO Pa kin models, S ephenson e al. [137] ied a no el app oach by c ea ing a double KO o Pa kin and Pa kin co- egula ed gene (PACRG). Pa kin and PACRG sha e a bidi ec ional p omo e , wi h he ansc ip ional s a si es being app oxima ely 200bp apa . Howe e , no abno mali ies o he dopamine gic sys em in he subs an- ia nig a and no loss o neu ons we e ound. Analysis o PARKIN and i s subs a es has yielded pos- sible PD associa ed neu odegene a i e mechanisms. PARKIN media es he ubiqui ina ion and p o easome- dependen deg ada ion o synap o agmin-11 (Sy 11) unde no mal condi ions [138]. Sy 11 is a no el isk gene in ol ed in PD whose accumula ion in dopamine gic neu ons due o PARKIN dys unc ion inhibi s endocy osis and hence dopamine elease leading o neu o oxici y [40, 138]. In e es ingly, Wang e al. [138] ound ha knock- down o Sy 11 in Pa kin knockdown backg ound lead o he eco e y o he dopamine elease in he subs an- ia nig a. PARKIN also media es he ubiqui ina ion and p o easome-dependen deg ada ion o Zinc inge p o- ein 746 (ZNF746, also known as PARIS) unde no mal condi ions [139]. Accumula ion o ZNF76 occu s due o PARKIN inac i a ion and is p esen in PD human b ain samples [139, 140]. ZNF746 is a ansc ip ional ep es- so o pe oxisome p oli e a o -ac i a ed ecep o -gamma (PPARγ) coac i a o -1α (PGC-1α) exp ession and i s a - ge gene nuclea espi a o y ac o 1 (NRF-1). In Pa kin KO animals, dopamine gic neu ons loss was ound o be in a ZNF746-dependen manne wi h i s o e exp es- sion leading o dopamine gic neu onal loss in he sub- s an ia nig a [139]. Recen ly, B ahmacha i e  al. [140] ound ha ZNF746 is a pi o al media o o α-synuclein induced neu odegene a ion a ec ing bo h dopamine gic and non-dopamine gic neu ons. In α-synuclein o e - exp ession mouse models c-Abl kinase phospho yla- ion o PARKIN led o he impai men o i s ac i i y and subsequen accumula ion o ZNF746. Impo an ly, hey ound ha abla ion o ZNF746 leads o he escue o he neu odegene a i e pheno ype obse ed in α-synuclein models o amilial and spo adic PD [140]. PARKIN inac- i a ion also leads o he accumula ion o ano he one o i s subs a es, aminoacyl- RNA syn he ase complex in e ac ing mul i unc ional p o ein-2 (AIMP2), ound o be inc eased in Pa kin KO mouse models and PD b ain samples [140–143]. AIMP2 o e exp ession causes a p o- g essi e and degene a i e loss o dopamine gic neu ons due o Poly(ADP- ibose) polyme ase-1 (PARP1) o e ac i a ion. PARP1 inhibi ion in he AIMP2 o e exp essed mouse model was p o ec i e and p e en ed degene a ion o dopamine gic neu ons [141]. Ou side i s ole as an E3 ubiqui in ligase in ol ed in mi ophagy, PARKIN also has a ole in ansc ip ional egula ion ( e iewed by Cos a e al. [144]). As an exam- ple, PARKIN has been ound o unde go nuclea ans- loca ion upon DNA damage whe e i may play a ole in he ansc ip ional con ol o DNA epai mechanisms such as base and nucleo ide excision epai and double s and b eak epai [145]. The ansc ip ion ac o ole o PARKIN he e o e may ac as a cellula de ense mecha- nism agains geno oxici y and sugges s ha DNA dam- age plays a pa hogenic ole in neu odegene a i e disease such as PD [144, 145]. Recen ly, Shi es e al. [146] ha e Page 9 o 20 Quinne al. ac a neu opa hol commun (2020) 8:189 iden i ied a ole o nuclea PARKIN du ing hypoxia in ac i a ion o es ogen- ela ed ecep o α (ERRα), which is a ansc ip ion ac o associa ed wi h mi ochond ial me abolism and biogenesis. In e es ingly, hey also ound ha PARKIN mu an s, Pa kinR42P and Pa kinG430D, a e excluded om he nucleus and he e o e unable o induce he ansc ip ion ac o ole o PARKIN. The e- o e, he ansc ip ional oles as well as he mi ophagic oles o PARKIN should be conside ed in PD as well as o he neu odegene a i e condi ions.A Pink1 KO mouse model in which he pa hogenic pa ien mu a ion G309D was inse ed in o exon 5 p esen ed mi ochond ial dys- unc ion leading o de ec s in ATP gene a ion along wi h a educ ion in dopamine in he nig os ia al p ojec ion wi h a concu en educ ion in locomo o ac i i y, bu again wi hou neu odegene a ion [132]. Gene a ion o a u he Pink1 KO mouse, whe e exons 4–7 we e dele ed and consequen ly he majo i y o he kinase domain was emo ed, c ea ing a nonsense mu a ion, caused impai men o dopamine elease wi h s ia al plas ic- i y educ ion. These impai men s we e escued ei he in he p esence o dopamine ecep o agonis s o due o s imula ion o dopamine elease, again highligh ing he ele ance o he nig os ia al ci cui [134]. In he same Pink1 KO mouse model, i was shown ha eloca ion o PARKIN o mi ochond ia induced by a collapse o Δψm elies on PINK1 exp ession [147]. In ano he Pink1 KO mouse model, whe e exon 2 o exon 5 we e eplaced wi h a LacZ/Neo casse e, impai ed dopamine elease was also ound. As compa ed o wild- ype, dopamine om s ia al slices o Pink1 KO mice dec eased in an age-dependen manne . Addi ionally, i was ound an age-dependen dec ease in basal oxygen consump ion a es and ATP le els in Pink1 KO mice, which sugges s ha dec eased ATP gene a ion may be he cause o he dec eased dopa- mine elease [148]. Recen ly, silencing o Pink1 in cul- u ed mouse hippocampal neu ons caused a dec ease in pos synap ic densi y p o eins PSD95 and Shank as well as glu ama e ecep o subuni NR2B and mGluR5. In e - es ingly, he au ho s ound changes in ac in egula o y p o eins RhoGAP29 and ROCK2 which we e concu en wi h changes in spine mo phology. The changes in den- d i ic spines, showing inc eased hin densi y spines and educed head size o s ubby spines, may be a sign o p e- symp oma ic changes ha lead o neu odegene a ion in PD [149]. In compa ison, a Pink1 KO a model showed nig al neu odegene a ion wi h 50% dopamine gic cell loss, an inc ease in s ia al dopamine and se o onin con- en and signi ican mo o de ici s [136]. The inabili y o oden models o ecapi ula e he se e e neu odegene a ion seen in PD pa ien s may be due o low le els o PINK1, as has been iden i ied in mice [150]. These s udies also sugges he e may be PINK1 independen mi ophagy pa hways ye o be eluded oo. Recen ly, CRISPR/Cas9-media ed Pink1 dele ion in he- sus macaques igge ed se e e neu odegene a ion o he co ex, s ia um and subs an ia nig a, wi h se e al new- bo ns dying sho ly a e bi h [151, 152]. These da a sug- ges ha in humans ull PINK1 loss may lead o le hali y in ea ly de elopmen . In e es ingly, a KO mouse model o he PINK1 OMM s abilisa ion p o ein PGAM5 leads o a mo e se e e PD-like animal model han in Pink1 KO mouse models. The Pgam5 KO mice show a signi i- can degene a ion in dopamine gic neu ons in addi ion o a PD-like mo emen diso de cha ac e ised by gai changes and b adykinesia [80]. Las ly, in ligh o mi ochond ia’s ole in he immune sys em, we should look o eassess he many diso - de s associa ed wi h de ec i e mi ochond ial genes in e ms o po en ial au oimmuni y. PD, as one example, has been ecen ly ho ly deba ed as also being an au o- immune disease [153–158]. PINK1 and PARKIN ha e been ound o egula e adap i e immuni y, being key o mi ochond ial an igen p esen a ion in a mi ophagy independen p ocess. This p ocess ins ead elies on he gene a ion o MDVs wi h a di ec co ela ion be ween he ex en o MDV o ma ion and he amoun o mi o- chond ial an igen p esen a ion. PINK1 and PARKIN inhibi his p ocess, he p esence o PARKIN was ound o be key in p e en ing Snx9 being ec ui ed o mi o- chond ia and ini ia ing MDV o ma ion [159]. Fu he suppo ing his no ion, i was ecen ly ound ha in es- inal in ec ion o Pink1 KO mice wi h G am-nega i e bac e ia elici ed mi ochond ial an igen p esen a ion and au oimmune mechanisms. These esponses igge ed mi ochond ial-speci ic CD8+ T-cells ha we e ound o induce dopamine gic neu on dea h. The in ec ed Pink1 KO mice p esen ed acu e mo o symp oms [153]. The a- peu ics ha in luence mi ochond ial immune egula ion will be an exci ing a ea o be de eloped in ea ing hese diseases. Amyo ophic la e al scle osis is a p og essi e and debili a ing neu omuscula disease ma ked by degene a- ion o mo o neu ons in he b ain and spinal co d, lead- ing o muscle a ophy, pa alysis and o dea h 3–5yea s a e disease onse . Mi ochond ial dys unc ion has been associa ed wi h ALS, wi h causa i e genes including au ophagy adap o s OPTN and SQSTM1, and au ophagy enhance TBK1 [160–163]. Al e ed exp ession le els o mRNA and p o ein o PINK1 ha e been iden i ied in human ALS pa ien s muscle [164]. Mu a ions in supe ox- ide dismu ase 1 (SOD1) gene a e associa ed wi h amilial ALS [165]. A SOD1G93A ALS mouse model exhibi s dys- egula ed PINK1 and PARKIN and p og essi e de ec s in mi ochond ial unc ion and dynamics [47, 164]. In spi- nal co d mo o neu ons o he SOD1G93A mouse model Page 16 o 20 Quinne al. ac a neu opa hol commun (2020) 8:189 Re e ences 1. Benda C (1898) Uebe die Spe ma ogenese de Ve beb a en und höhe e E e eb a en, II. Theil: die His iogenese de Spe mien. A ch Ana Physiol A ch Ana Physiol 73:393–398 2. Be na d G, Bellance N, James D, Pa one P, Fe nandez H, Le ellie T e al (2007) Mi ochond ial bioene ge ics and s uc u al ne wo k o ganiza- ion. J Cell Sci 120(5):838–848 3. 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