PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis

Weili Yang, Xiangyu Guo, Zhuchi Tu, Xiusheng Chen, Rui Han, Yanting Liu, Sen Yan, Qi Wang, Zhifu Wang, Xianxian Zhao, Yunpeng Zhang, Xin Xiong, Huiming Yang, Peng Yin, Huida Wan, Xingxing Chen, Jifeng Guo, Xiao-Xin Yan, Lujian Liao, Shihua Li, Xiao-Jiang Li

PDF(13744 KB)
PDF(13744 KB)
Protein Cell ›› 2022, Vol. 13 ›› Issue (1) : 26-46. DOI: 10.1007/s13238-021-00888-x
RESEARCH ARTICLE

PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis

Author information +
History +

Abstract

In vitro studies have established the prevalent theory that the mitochondrial kinase PINK1 protects neurodegeneration by removing damaged mitochondria in Parkinson's disease (PD). However, difficulty in detecting endogenous PINK1 protein in rodent brains and cell lines has prevented the rigorous investigation of the in vivo role of PINK1. Here we report that PINK1 kinase form is selectively expressed in the human and monkey brains. CRISPR/Cas9-mediated deficiency of PINK1 causes similar neurodegeneration in the brains of fetal and adult monkeys as well as cultured monkey neurons without affecting mitochondrial protein expression and morphology. Importantly, PINK1 mutations in the primate brain and human cells reduce protein phosphorylation that is important for neuronal function and survival. Our findings suggest that PINK1 kinase activity rather than its mitochondrial function is essential for the neuronal survival in the primate brains and that its kinase dysfunction could be involved in the pathogenesis of PD.

Keywords

Parkinson's disease / neurogenesis / neurodegeneration / mitochondria / non-human primates

Cite this article

Download citation ▾
Weili Yang, Xiangyu Guo, Zhuchi Tu, Xiusheng Chen, Rui Han, Yanting Liu, Sen Yan, Qi Wang, Zhifu Wang, Xianxian Zhao, Yunpeng Zhang, Xin Xiong, Huiming Yang, Peng Yin, Huida Wan, Xingxing Chen, Jifeng Guo, Xiao-Xin Yan, Lujian Liao, Shihua Li, Xiao-Jiang Li. PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis. Protein Cell, 2022, 13(1): 26‒46 https://doi.org/10.1007/s13238-021-00888-x

References

[1]
AkundiRS, HuangZ, EasonJ, Pandya JD, ZhiL, CassWA, Sullivan PG, BüelerH (2011) Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS ONE 6:e16038
CrossRef Google scholar
[2]
Al-RumayyanA, KleinC, AlfadhelM (2017) Early-onset parkinsonism: case report and review of the literature. Pediatr Neurol 67:102–106.e1
CrossRef Google scholar
[3]
ArenaG, Valente EM (2017) PINK1 in the limelight: multiple functions of an eclectic protein in human health and disease. J Pathol 241:251–263
CrossRef Google scholar
[4]
BentivoglioAR, Cortelli P, ValenteEM, IalongoT, Ferraris A, EliaA, MontagnaP (2001) Phenotypic characterisation of autosomal recessive PARK6-linked parkinsonism in three unrelated Italian families. Mov Disord 16:999–1006
CrossRef Google scholar
[5]
BonifatiV, RoheCF, BreedveldGJ, Fabrizio E, De MariM, TassorelliC, Tavella A, MarconiR, NichollDJ, ChienHF et al (2005) Earlyonset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology 65:87–95
CrossRef Google scholar
[6]
BraakH, Müller CM, RübU, AckermannH, Bratzke H, De VosRA, Del TrediciK (2006) Pathology associated with sporadic Parkinson’s disease—where does it end. J Neural Transm Suppl 89–97
CrossRef Google scholar
[7]
ChenZZ, WangJY, KangY, Yang QY, GuXY, ZhiDL, YanL, LongCZ, Shen B, NiuYY et al (2021) PINK1 gene mutation by pair truncated sgRNA/Cas9-D10A in cynomolgus monkeys. ZoolRes 42:469–477
CrossRef Google scholar
[8]
ChuCT (2019) Multiple pathways for mitophagy: a neurodegenerative conundrum for Parkinson’s disease. Neurosci Lett 697:66–71
CrossRef Google scholar
[9]
ClarkIE, DodsonMW, JiangC, Cao JH, HuhJR, SeolJH, YooSJ, HayBA, Guo M (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441:1162–1166
CrossRef Google scholar
[10]
CondorelliF, Salomoni P, CotteretS, CesiV, Srinivasula SM, AlnemriES, CalabrettaB (2001) Caspase cleavage enhances the apoptosis-inducing effects of BAD. Mol Cell Biol 21:3025–3036
CrossRef Google scholar
[11]
CortiO, LesageS, BriceA (2011) What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev 91:1161–1218
CrossRef Google scholar
[12]
CumminsN, GotzJ (2018) Shedding light on mitophagy in neurons: what is the evidence for PINK1/Parkin mitophagy in vivo? Cell Mol Life Sci 75:1151–1162
CrossRef Google scholar
[13]
DattaSR, RangerAM, LinMZ, Sturgill JF, MaYC, CowanCW, DikkesP, KorsmeyerSJ, Greenberg ME (2002) Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Dev Cell 3:631–643
CrossRef Google scholar
[14]
DaveKD, De Silva S, ShethNP, RambozS, BeckMJ, QuangC, Switzer RC III, AhmadSO, SunkinSM, WalkerD et al (2014) Phenotypic characterization of recessive gene knockout rat models of Parkinson’s disease. Neurobiol Dis 70:190–203
CrossRef Google scholar
[15]
de HaasR, Heltzel LCMW, TaxD, van den BroekP, Steenbreker H, VerheijMM, RusselFG, OrrAL, NakamuraK, Smeitink JA et al (2019) To be or not to be pink(1): contradictory findings in an animal model for Parkinson’s disease. Brain Commun 1:fcz016
CrossRef Google scholar
[16]
de VriesRLA, Przedborski S (2013) Mitophagy and Parkinson’s disease: be eaten to stay healthy. Mol Cell Neurosci 55:37–43
CrossRef Google scholar
[17]
GispertS, Ricciardi F, KurzA, AzizovM, Hoepken HH, BeckerD, VoosW, LeunerK, MüllerWE, KudinAP et al (2009) Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS ONE 4:e5777
CrossRef Google scholar
[18]
GladkovaC, MaslenSL, SkehelJM, Komander D (2018) Mechanism of parkin activation by PINK1. Nature 559:410–414
CrossRef Google scholar
[19]
HanH, TanJ, WangR, Wan H, HeY, YanX, GuoJ, GaoQ, LiJ, ShangS et al (2020) PINK1 phosphorylates Drp 1(S616) to regulate mitophagy-independent mitochondrial dynamics. EMBO Rep 21:e48686
CrossRef Google scholar
[20]
Ishihara-PaulL, Hulihan MM, KachergusJ, UpmanyuR, WarrenL, AmouriR, Elango R, PrinjhaRK, SotoA, KefiM et al (2008) PINK1 mutations and parkinsonism. Neurology 71:896–902
CrossRef Google scholar
[21]
KitadaT, PisaniA, PorterDR, Yamaguchi H, TscherterA, MartellaG, BonsiP, ZhangC, Pothos EN, ShenJ et al (2007) Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci USA 104:11441–11446
CrossRef Google scholar
[22]
KoyanoF, OkatsuK, KosakoH, Tamura Y, GoE, KimuraM, KimuraY, TsuchiyaH, Yoshihara H, HirokawaT et al (2014) Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 510:162–166
CrossRef Google scholar
[23]
LangstonJW (2006) The Parkinson’s complex: parkinsonism is just the tip of the iceberg. Ann Neurol 59:591–596
CrossRef Google scholar
[24]
LazarouM, SliterDA, KaneLA, Sarraf SA, WangC, BurmanJL, Sideris DP, FogelAI, YouleRJ (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–314
CrossRef Google scholar
[25]
LeeJJ, Sanchez-Martinez A, ZarateAM, BenincáC, MayorU, ClagueMJ, Whitworth AJ (2018) Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin. J Cell Biol 217:1613–1622
CrossRef Google scholar
[26]
LiH, WuS, MaX, LiX, ChengT, Chen Z, WuJ, LvL, LiL, XuL et al (2021) Co-editing PINK1 and DJ-1 genes via adeno-associated virus-delivered CRISPR/Cas9 system in adult monkey brain elicits classical parkinsonian phenotype. Neurosci Bull 37:1271–1288
CrossRef Google scholar
[27]
MarongiuR, Ferraris A, IalongoT, MichiorriS, SoletiF, FerrariF, Elia AE, GhezziD, AlbaneseA, Altavista MC et al (2008) PINK1 heterozygous rare variants: prevalence, significance and phenotypic spectrum. Hum Mutat 29:565
CrossRef Google scholar
[28]
MatheoudD, CannonT, VoisinA, Penttinen AM, RametL, FahmyAM, DucrotC, LaplanteA, Bourque MJ, ZhuL et al (2019) Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1(-/-) mice. Nature 571:565–569
CrossRef Google scholar
[29]
McInerney-LeoA, HadleyDW, Gwinn-HardyK, HardyJ (2005) Genetic testing in Parkinson’s disease. Mov Disord 20:1–10
CrossRef Google scholar
[30]
McWilliamsTG, Prescott AR, Montava-GarrigaL, BallG, SinghF, BariniE, Muqit MM, BrooksSP, GanleyIG (2018) Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand. Cell Metab 27:439–449.e5
CrossRef Google scholar
[31]
NarendraDP, JinSM, TanakaA, Suen DF, GautierCA, ShenJ, Cookson MR, YouleRJ (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298
CrossRef Google scholar
[32]
O’FlanaganCH, O’Neill C (2014) PINK1 signalling in cancer biology. Biochim Biophys Acta 1846:590–598
CrossRef Google scholar
[33]
OkatsuK, OkaT, IguchiM, Imamura K, KosakoH, TaniN, KimuraM, GoE, KoyanoF, FunayamaM et al (2012) PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria. Nat Commun 3:1016
CrossRef Google scholar
[34]
OrdureauA, HeoJM, DudaDM, Paulo JA, OlszewskiJL, YanishevskiD, Rinehart J, SchulmanBA, HarperJW (2015) Defining roles of PARKIN and ubiquitin phosphorylation by PINK1 in mitochondrial quality control using a ubiquitin replacement strategy. Proc Natl Acad Sci USA 112:6637–6642
CrossRef Google scholar
[35]
PickrellAM, YouleRJ (2015) The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85:257–273
CrossRef Google scholar
[36]
QiuW, ZhangH, BaoA, ZhuK, HuangY, Yan X, ZhangJ, ZhongC, ShenY, ZhouJ et al (2019) Standardized operational protocol for human brain banking in China. Neurosci Bull 35:270–276
CrossRef Google scholar
[37]
ScarffeLA, Stevens DA, DawsonVL, DawsonTM (2014) Parkin and PINK1: much more than mitophagy. Trends Neurosci 37:315–332
CrossRef Google scholar
[38]
TrinhJ, FarrerM (2013) Advances in the genetics of Parkinson disease. Nat Rev Neurol 9:445–454
CrossRef Google scholar
[39]
TuZ, YangW, YanS, YinA, GaoJ, LiuX, ZhengY, Zheng J, LiZ, YangS et al (2017) Promoting Cas9 degradation reduces mosaic mutations in non-human primate embryos. Sci Rep 7:42081
CrossRef Google scholar
[40]
ValenteEM, Abou-Sleiman PM, CaputoV, MuqitMM, HarveyK, GispertS, Ali Z, Del TurcoD, BentivoglioAR, HealyDG et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160
CrossRef Google scholar
[41]
VoigtA, Berlemann LA, WinklhoferKF (2016) The mitochondrial kinase PINK1: functions beyond mitophagy. J Neurochem 139 (Suppl):232–239
CrossRef Google scholar
[42]
WalshTG, van den Bosch MT, LewisKE, WilliamsCM, PooleAW (2018) Loss of the mitochondrial kinase PINK1 does not alter platelet function. Sci Rep 8:14377
CrossRef Google scholar
[43]
WanH, TangB, LiaoX, Zeng Q, ZhangZ, LiaoL (2018) Analysis of neuronal phosphoproteome reveals PINK1 regulation of BAD function and cell death. Cell Death Differ 25:904–917
CrossRef Google scholar
[44]
WangX, CaoC, HuangJ, Yao J, HaiT, ZhengQ, WangX, ZhangH, Qin G, ChengJ (2016) One-step generation of triple genetargeted pigs using CRISPR/Cas9 system. Sci Rep 6:20620
CrossRef Google scholar
[45]
WhitworthAJ, Pallanck LJ (2017) PINK1/Parkin mitophagy and neurodegeneration-what do we really know in vivo? Curr Opin Genet Dev 44:47–53
CrossRef Google scholar
[46]
XiongH, WangD, ChenL, Choo YS, MaH, TangC, XiaK, JiangW, Ronai ZE, ZhuangX et al (2009) Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J Clin Invest 119:650–660
CrossRef Google scholar
[47]
YamanoK, YouleRJ (2013) PINK1 is degraded through the N-end rule pathway. Autophagy 9:1758–1769
CrossRef Google scholar
[48]
YanXX, MaC, BaoAM, Wang XM, GaiWP (2015) Brain banking as a cornerstone of neuroscience in China. Lancet Neurol 14:136
CrossRef Google scholar
[49]
YanS, TuZ, LiuZ, FanN, YangH, Yang S, YangW, ZhaoY, OuyangZ, LaiC et al (2018) A huntingtin knockin pig model recapitulates features of selective neurodegeneration in huntington’s disease. Cell 173:989–1002.e13
CrossRef Google scholar
[50]
YangW, WangG, WangCE, Guo X, YinP, GaoJ, TuZ, WangZ, Wu J, HuX et al (2015) Mutant alpha-synuclein causes age-dependent neuropathology in monkey brain. J Neurosci 35:8345–8358
CrossRef Google scholar
[51]
YangS, ChangR, YangH, Zhao T, HongY, KongHE, SunX, QinZ, JinP, LiS et al (2017) CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease. J Clin Invest 127:2719–2724
CrossRef Google scholar
[52]
YangW, LiS, LiX-J (2019a) A CRISPR monkey model unravels a unique function of PINK1 in primate brains. Mol Neurodegener 14:17
CrossRef Google scholar
[53]
YangW, LiuY, TuZ, XiaoC, YanS, MaX, GuoX, ChenX, YinP, YangZ (2019b) CRISPR/Cas9-mediated PINK1 deletion leads to neurodegeneration in rhesus monkeys. Cell Res 29:334–336
CrossRef Google scholar
[54]
ZhouX, XinJ, FanN, ZouQ, HuangJ, Ouyang Z, ZhaoY, ZhaoB, LiuZ, LaiS et al (2015) Generation of CRISPR/Cas9-mediated gene-targeted pigs via somatic cell nuclear transfer. Cell Mol Life Sci 72:1175–1184
CrossRef Google scholar

RIGHTS & PERMISSIONS

2021 The Author(s)
AI Summary AI Mindmap
PDF(13744 KB)

Accesses

Citations

Detail

Sections
Recommended

/