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
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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
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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.
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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
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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]
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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

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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
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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
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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
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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
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Publishe ’s No e
Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in pub-
lished maps and ins i u ional a ilia ions.