Submitted Successfully!
Thank you for your contribution! You can also upload a video entry related to this topic through the link below:
Check Note
Ver. Summary Created by Modification Content Size Created at Operation
1 + 2189 word(s) 2189 2021-11-10 10:22:39 |
2 Format change Meta information modification 2189 2021-11-22 02:57:15 |
The Role of PINK1 in Parkinson’s Disease
Upload a video

The progressive reduction of the dopaminergic neurons of the substantia nigra is the
fundamental process underlying Parkinson’s disease (PD), while the mechanism of susceptibility
of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have
been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain
impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on
the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced
putative kinase 1) gene mutations, although rare, are the second most common cause of
recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and
Parkin function has increased dramatically in the last years, with the discovery that a process
called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated
by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the
role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of
paramount importance to further define the role of PINK1 in mitophagy and mitochondrial
homeostasis in PD pathogenesis in order to delineate novel therapeutic targets.

  • PINK1
  • Parkinson’s disease
Subjects: Allergy
Contributor :
View Times: 48
Revisions: 2 times (View History)
Update Time: 22 Nov 2021

1. Background

Parkinson’s disease (PD) is the second most common degenerative neurological disorder after Alzheimer’s disease. It is caused by the prominent progressive degeneration of the dopaminergic neurons of the substantia nigra (SN) pars compacta. Molecular mechanisms underlying the degeneration of this specific neuronal population are still largely unclear, but it is known that these cells have a large axonal architecture and a so-called pacemaking activity, which puts them under an extreme bioenergetic demand for the propagation of action potentials, maintenance of membrane potential and synaptic transmission [1][2]. These distinctive features account for the essential role of mitochondrial dysfunction in PD pathogenesis, as demonstrated by the finding that exposure to environmental mitochondrial toxins leads to PD-like pathology [3].
Evidence of this is that PINK1 and Parkin, both involved in mitochondrial dynamics and quality control, are the main cause of autosomal recessive (AR) early-onset PD [4][5][6]. Their molecular role has been extensively studied in the last few years, revealing that the PINK1-Parkin pathway is responsible for the selective degradation of damaged mitochondria, which is necessary for the maintenance of mitochondrial homeostasis, especially in non-dividing cells, such as neurons.

2. PINK1 Protein Functions

PINK1 encodes a 581 acid serine/threonine-type protein kinase localized primarily in mitochondria, where it plays a pivotal role in regulating mitochondrial quality control (mitoQC), promoting maintenance of respiring mitochondrial networks, and regulating the selective elimination of damaged mitochondria via autophagy, a process known as mitophagy [7].
Aside from its role in mitochondrial quality control, PINK1 is also known to have a pro-survival role in preventing neuronal cell death in response to various stress conditions [5][8][9].
PINK1 protein is composed of a highly conserved Ser/Thr kinase domain flanked by a C-terminal, a transmembrane sequence (TMS, or TMD, transmembrane domain), and an N-terminal mitochondrial targeting sequence (MTS) [10] (Figure 1).
Figure 1. Domain architecture of PINK1 (581 amino acids). Mitochondrial targeting sequence (MTS, orange), transmembrane domain (TMD, blue).
PINK1 kinase domain consists of amino- and carboxy-terminal lobes (N-and C-lobes), but it also has a unique feature, that is the presence of three amino acid sequences—called insertions, in addition to an unusual domain in the C-terminal region (CTR) that is not found in any other protein kinase [11].
Kumar et al. [12] and Schubert et al. [13] in 2017 observed that insertion 2 contains a β-strand and an á-helix which relocate the N-lobe next to the so-called áC helix, a conserved key regulatory region of many protein kinases; this region is likely to play a role in regulating PINK1 enzymatic activity.
Moreover, the CTR and the C lobe share a hydrophobic core which explains why CTR and the kinase domain cannot be drawn apart. For what concerns insertion 3, Schubert et al. [13] described its role in substrate binding: mutations in this insertion impair ubiquitin-like domain (UBL) and ubiquitin phosphorylation, but do not affect PINK1 autophosphorylation.
Limited information is available, instead, about the role of both CTR and insertion 1.
According to both Kumar and Schubert models, most of the disease-causing PINK1 mutations associated with PD may act altering PINK1 or selectively impairing its catalysis, phosphoregulation, or substrate binding [11].
Elucidating the mechanisms that underlie the physiological and pathological PINK1 functioning will provide a rationale for the identification of potential PD-modifying treatments.
Dopaminergic neurons in both PD and aged individuals display dysfunctional mitochondria accumulating high levels of mitochondrial DNA (mtDNA) deletions [14][15].
Mitochondrial function impairment is strongly implicated in the etiology of PD: the first evidence for mitochondrial involvement in PD pathogenesis was the finding that chemical inhibition of mitochondrial Complex I could reproduce Parkinsonism in humans and animals [16][17], because inhibition of this complex induces both depletion of ATP and generation of ROS which causes oxidative stress. Moreover, the administration of the mitochondrial respiratory poison MPTP (1-methyl-4-phenyl-1-1,2,3,6-tetrahydropyridine) in mice induces symptoms similar to those observed in sporadic PD.
All the four principal genes implicated in autosomal recessive EOPD-PRKN, PINK1, DJ-1, and VPS13C—are involved in mitochondrial homeostasis and mitophagy.
In healthy mitochondria, under normal conditions, PINK1 levels are often repressed due to its translocation to the inner mitochondrial membrane (IMM), where its two domains MTS and TMS are cleaved off by, respectively, MPP (mitochondria processing peptidase) [18] and PARL (Presenilin-associated rhomboid-like protein) [19]. When deprived of MTS and TMS, the resulting 52 kDa processed PINK1 is transferred to the cytoplasm and then degraded by the ubiquitin-proteasome system [20]. In response to mitochondrial stress/depolarization, the altered IMM prevents MTS and TMS from being cleaved. Full-length PINK1 is stabilized and accumulates on the mitochondrial outer membrane (OMM) where it forms a multimeric complex with outer-membrane proteins, the TOM machinery, and self-phosphorylates on Ser228, Thr257, and Ser402 to fully activate its kinase domain [21]. Activated PINK1 phosphorylates Parkin at Serine65 (Ser65) in the N-terminal ubiquitin-like (UBL) domain, to activate Parkin enzymatic function and induce Parkin recruitment into the OMM of the damaged mitochondria [22][23]. Accumulation of PINK1 is crucial as a mitochondrial damage sensor, but the molecular mechanisms underlying its association with the TOM complex remain unclear [24].
Moreover, PINK1 is also known to phosphorylate ubiquitin itself at Ser65, which then binds to the RING1 domain of Parkin with high affinity [25][26][27], facilitating its conformational rearrangements and enzymatic activation.
For full activation of Parkin, phosphorylation of both the N-terminal UBL Ser65 residue of Parkin and ubiquitin is required.
Activated Parkin further attaches ubiquitin to neighboring OMM proteins so that PINK1 can recognize them as damaged proteins and phosphorylate them, which in turn amplifies Parkin activation and recruitment [28]. PINK1/Parkin conjugated actions cause damaged mitochondria to be coated with phosphorylated Ser65-ubiquitin chains and headed towards degradation into the proteasome.
Regarding PINK1 regulation, another important role is that of phosphatase PTEN, a de-phosphorylating intracellular enzyme that negatively regulates the activity of many protein kinases. PTEN-L splicing variant, which contains an additional domain in its N-terminal, is generally located in the OMM, where its activation antagonizes PINK1-mediated phosphorylation of Parkin-UBL and ubiquitin, thus blocking mitophagy [29].
PINK1 also coordinates several aspects of mitochondrial quality control, influencing the clearance of a wide range of substrates. Growing evidence suggests that PINK1 and Parkin are crucial for modulating mitochondrial fission and fusion, which balance is critical for the mitochondrial network. Indeed, it is known that ubiquitination of mitofusins (MFN) 1 and 2 is an early event in the PINK1-Parkin-dependent pathway. The MFN are transmembrane GTPases located in the OMM and implicated in the fusion of mitochondria. Their Parkin-dependent ubiquitination and subsequent proteasomal degradation prevent them from promoting damaged mitochondrial refusion [30]. This process further leads to fragmentation of damaged mitochondria [31], thus promoting mitophagy. The first hypothesis about MFN-1/-2 in mitophagy is that PINK1/Parkin-dependent ubiquitination of MFNs could induce the recruitment of ubiquitin-binding proteins which could, in turn, activate the formation of autophagosomes for damaged mitochondria; alternatively, ubiquitination of MFNs could degrade the pro-fusion proteins preventing the refusion of depolarized/damaged mitochondria with the mitochondrial network, thus contributing to segregate damaged mitochondria for degradation by mitophagy [32].
PINK1 deficiency also affects Complex I activity, thus disrupting respiratory chain function and increasing cell susceptibility to apoptosis [33]: Morais et al. [34] described that Complex I phosphorylation mediated by PINK1 is essential for ubiquinone reduction to regulate mitochondrial bioenergetics. The disruption in respiratory chain function results in cellular ATP deficiency and subsequent reduction in mitochondrial membrane potential (ÄØm), which induces Parkin translocation to the OMM, where it ubiquitinates various OMM proteins and promotes the selective removal of damaged mitochondria (mitophagy). Moreover, the use of the uncoupler CCCP (carbonyl cyanide m-chlorophenyl hydrazone) in mammalian cells reduces ÄØm, inducing Parkin translocation to the OMM and damaged mitochondria elimination via mitophagy.
Aside from their role in mitophagy and mitochondrial quality control, both Parkin and PINK1 have independent pro-survival activities and can prevent neuronal cell death in several stress paradigms [35].
In 2012, Soubannier et al. [36] firstly described an additional role of the PINK1/Parkin pathway in the regulation of a selective form of mitochondrial quality control, based on the presence of cargo-selective mitochondria-derived vesicles (MDVs). MDVs bud off mitochondria and are responsible for the degradation of damaged and oxidized mitochondrial proteins and lipid cargo into peroxisomes and other specific cargos into lysosomes, in a way that is independent of autophagy. Interestingly, at least part of MDVs trafficking is mediated by the vacuolar protein sorting 35 homolog gene (VPS35) [37], which is known to be associated with late-onset autosomal dominant PD (PARK17) [38][39].
More recent studies showed the existence of an intimate connection between mitochondria and other organelles, particularly the endosomal compartment [40][41][42].
Even if little is known about this complex interaction, it is likely that it plays a crucial role in influencing many mitochondrial functions, some of them regarding mitochondrial quality control processes and the release of MDVs. In fact, many proteins involved in endocytosis are also part of the process that regulates mitochondrial fission and fusion and, on the other hand, PINK1 and Parkin widely contribute to regulate mitochondrial quality control mediated by the lysosomal-dependent degradation of dysfunctional and damaged mitochondria. In this setting, PINK1-related mitochondrial dysfunction promptly results in the accumulation of altered endosomal components [43], thus suggesting this cross-talk represents an efficient and important way for metabolites to be recycled [44].
Nevertheless, the exact mechanisms through which mitochondria-endosome cross-talking occurs in mammalians is still unclear, as well as its implications in physiological and pathological conditions, thus limiting so far our chance to outline its possible role in PINK1-related mitochondrial impairment.
PINK1 overexpression has also been associated with reduced toxin-mediated cell death, supporting the hypothesis of a pro-survival role of this protein [45][46]. On the other hand, PINK1 KO mice show increased vulnerability to the complex I inhibitor MPTP, which moreover can be rescued by Parkin [47].
Of note, cytosolic PINK1 cannot promote mitophagy [48], suggesting that PINK1 pro-survival activity and its mitophagy-inducing role cannot be detached [35].
In a neuronal cell culture model for synucleinopathy, the downregulation of PINK1 enhanced alpha-synuclein aggregation and apoptosis.

3. Clinical Features and Genotype-Phenotype Correlation

As the other autosomal recessive EOPD forms, PINK1-associated PD is characterized by early onset of unilateral tremor, bradykinesia and rigidity that are often indistinguishable from other PD forms, especially PRKN and idiopathic PD. However, PINK1 patients often show uncommon characteristics which can help differential diagnosis, including hyperreflexia, dystonia at onset, early L-dopa induced dyskinesias, and psychiatric and behavioral disturbances.
The mean age of onset of PD symptoms is 33 years. Lower limb dystonia may be a presenting sign, or may develop during disease progression [49], and should raise the suspicion of PINK1-related PD. Nonmotor symptoms and sleep impairment are common in individuals with PINK1 type of young-onset PD [50]. Also, postural instability, hyperreflexia, cognitive-behavioral disturbances and especially psychiatric symptoms -including depression (17%), anxiety (10%), and psychosis—have been reported (see, accessed on 10 July 2021).
Except for GBA-PINK1 is the PD-associated gene showing the highest rate of cognitive impairment, mainly concerning attention and executive functions [51], while the prevalence of depression is comparable between PINK1 patients and idiopathic PD.
Disease progression is usually benign and L-dopa response is often marked and sustained, with a high risk of developing L-dopa induced fluctuations throughout the disease [52].
Of note, although PINK1-related PD is associated with homozygous or compound heterozygous mutations, different heterozygous mutations have been reported in PD patients and healthy controls [49][53][54], but the effect of these mutations and their potential role as a risk factor for PD is far from been understood. In the past decade, some authors reported a higher prevalence of heterozygous PINK1 rare variants in PD patients when compared to healthy controls [49][55][56], thus suggesting that also heterozygous PINK1 mutations may predispose to PD. Particularly, Puschmann et al. [57] reported a genetic association between heterozygous PINK1 p.G411S mutations and PD, providing both structural and functional evidence for a negative effect of the mutant protein thus interfering with wild-type PINK1 kinase activity.
However, a recent wide assessment of PINK1 variants in 13,708 PD patients and 362,850 controls published by Krohn et al. [58] found no supporting evidence regarding the role of heterozygous PINK1 mutations as a risk factor for PD.
In conclusion, the spectrum of PINK1-associated phenotypes needs further investigation, especially regarding genotype-phenotype correlates; in fact, no correlation between the type of variant and age at onset, clinical presentation, or disease progression has yet been observed [59].


  1. Pissadaki, E.K.; Bolam, J.P. The energy cost of action potential propagation in dopamine neurons: Clues to susceptibility in Parkinson’s disease. Front. Comput. Neurosci. 2013, 7, 13.
  2. Guzman, R.E.; Schwarz, Y.N.; Rettig, J.; Bruns, D. SNARE Force Synchronizes Synaptic Vesicle Fusion and Controls the Kinetics of Quantal Synaptic Transmission. J. Neurosci. 2010, 30, 10272–10281.
  3. Moore, D.J.; West, A.B.; Dawson, V.L.; Dawson, T.M. Molecular pathophysiology Of Parkinson’s disease. Annu. Rev. Neurosci. 2005, 28, 57–87.
  4. Narendra, D.; Tanaka, A.; Suen, D.-F.; Youle, R.J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 2008, 183, 795–803.
  5. Pickrell, A.M.; Youle, R.J. The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease. Neuron 2015, 85, 257–273.
  6. Yamano, K.; Matsuda, N.; Tanaka, K. The ubiquitin signal and autophagy: An orchestrated dance leading to mitochondrial degradation. EMBO Rep. 2016, 17, 300–316.
  7. McWilliams, T.G.; Muqit, M.M. PINK1 and Parkin: Emerging themes in mitochondrial homeostasis. Curr. Opin. Cell Biol. 2017, 45, 83–91.
  8. Winklhofer, K.F. Parkin and mitochondrial quality control: Toward assembling the puzzle. Trends Cell Biol. 2014, 24, 332–341.
  9. Durcan, T.M.; Fon, E.A. USP8 and PARK2/parkin-mediated mitophagy. Autophagy 2015, 11, 428–429.
  10. Eiyama, A.; Okamoto, K. PINK1/Parkin-mediated mitophagy in mammalian cells. Curr. Opin. Cell Biol. 2015, 33, 95–101.
  11. Daou, S.; Sicheri, F. Vivid views of the PINK1 protein. Nat. Cell Biol. 2017, 552, 38–39.
  12. Kumar, A.; Tamjar, J.; Waddell, A.D.; Woodroof, H.I.; Raimi, O.G.; Shaw, A.M.; Peggie, M.; Muqit, M.M.; Van Aalten, D.M. Structure of PINK1 and mechanisms of Parkinson’s disease-associated mutations. eLife 2017, 6, e29985.
  13. Schubert, A.F.; Gladkova, C.; Pardon, E.; Wagstaff, J.L.; Freund, S.M.V.; Steyaert, J.; Maslen, S.L.; Komander, D. Structure of PINK1 in complex with its substrate ubiquitin. Nat. Cell Biol. 2017, 552, 51–56.
  14. Bender, A.; Krishnan, K.J.; Morris, C.M.; Taylor, G.A.; Reeve, A.K.; Perry, R.H.; Jaros, E.; Hersheson, J.S.; Betts, J.; Klopstock, T.; et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. 2006, 38, 515–517.
  15. Kraytsberg, Y.; Kudryavtseva, E.; McKee, A.C.; Geula, C.; Kowall, N.W.; Khrapko, K. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet. 2006, 38, 518–520.
  16. Langston, J.W.; Ballard, P.A. Parkinson’s Disease in a Chemist Working with 1-Methyl-4-Phenyl-L,2,5,6-Tetrahydropyridine. N. Engl. J. Med. 1983, 309, 310.
  17. Schapira, A.; Cooper, J.; Dexter, D.; Jenner, P.; Clark, J.; Marsden, C. Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1989, 333, 1269.
  18. Greene, A.W.; Grenier, K.; Aguileta, M.A.; Muise, S.; Farazifard, R.; Haque, M.E.; McBride, H.M.; Park, D.S.; Fon, E.A. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep. 2012, 13, 378–385.
  19. Deas, E.; Plun-Favreau, H.; Gandhi, S.; Desmond, H.; Kjaer, S.; Loh, S.H.; Renton, A.E.; Harvey, R.; Whitworth, A.; Martins, L.M.; et al. PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum. Mol. Genet. 2010, 20, 867–879.
  20. Yamano, K.; Youle, R.J. PINK1 is degraded through the N-end rule pathway. Autophagy 2013, 9, 1758–1769.
  21. Lazarou, M.; Jin, S.M.; Kane, L.A.; Youle, R.J. Role of PINK1 Binding to the TOM Complex and Alternate Intracellular Membranes in Recruitment and Activation of the E3 Ligase Parkin. Dev. Cell 2012, 22, 320–333.
  22. Kondapalli, C.; Kazlauskaite, A.; Zhang, N.; Woodroof, H.I.; Campbell, D.G.; Gourlay, R.; Burchell, L.; Walden, H.; Macartney, T.J.; Deak, M.; et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol. 2012, 2, 120080.
  23. Chen, Y.; Dorn, G.W., II. PINK1-Phosphorylated Mitofusin 2 Is a Parkin Receptor for Culling Damaged Mitochondria. Science 2013, 340, 471–475.
  24. Tanaka, K. The PINK1–Parkin axis: An Overview. Neurosci. Res. 2020, 159, 9–15.
  25. Kane, L.A.; Lazarou, M.; Fogel, A.I.; Li, Y.; Yamano, K.; Sarraf, S.; Banerjee, S.; Youle, R.J. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J. Cell Biol. 2014, 205, 143–153.
  26. Kazlauskaite, A.; Martinez-Torres, R.J.; Wilkie, S.; Kumar, A.; Peltier, J.; Gonzalez, A.; Johnson, C.; Zhang, J.; Hope, A.G.; Peggie, M.; et al. Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK 1-dependent phosphorylation and activation. EMBO Rep. 2015, 16, 939–954.
  27. Sauvé, V.; Lilov, A.; Seirafi, M.; Vranas, M.; Rasool, S.; Kozlov, G.; Sprules, T.; Wang, J.; Trempe, J.; Gehring, K. A Ubl/ubiquitin switch in the activation of Parkin. EMBO J. 2015, 34, 2492–2505.
  28. Koyano, F.; Okatsu, K.; Kosako, H.; Tamura, Y.; Go, E.; Kimura, M.; Kimura, Y.; Tsuchiya, H.; Yoshihara, H.; Hirokawa, T.; et al. Ubiquitin is phosphorylated by PINK1 to activate parkin. Nat. Cell Biol. 2014, 510, 162–166.
  29. Wang, L.; Cho, Y.-L.; Tang, Y.; Wang, J.; Park, J.-E.; Wu, Y.; Wang, C.; Tong, Y.; Chawla, R.; Zhang, J.; et al. PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1–Parkin-mediated mitophagy. Cell Res. 2018, 28, 787–802.
  30. Thomas, R.E.; Andrews, L.A.; Burman, J.L.; Lin, W.-Y.; Pallanck, L.J. PINK1-Parkin Pathway Activity Is Regulated by Degradation of PINK1 in the Mitochondrial Matrix. PLoS Genet. 2014, 10, e1004279.
  31. Poole, A.C.; Thomas, R.E.; Yu, S.; Vincow, E.S.; Pallanck, L. The Mitochondrial Fusion-Promoting Factor Mitofusin Is a Substrate of the PINK1/Parkin Pathway. PLoS ONE 2010, 5, e10054.
  32. Gegg, M.E.; Schapira, A.H. PINK1-parkin-dependent mitophagy involves ubiquitination of mitofusins 1 and 2: Implications for Parkinson disease pathogenesis. Autophagy 2011, 7, 243–245.
  33. Morais, V.A.; Verstreken, P.; Roethig, A.; Smet, J.; Snellinx, A.; Vanbrabant, M.; Haddad, D.; Frezza, C.; Mandemakers, W.; Vogt-Weisenhorn, D.; et al. Parkinson’s disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function. EMBO Mol. Med. 2009, 1, 99–111.
  34. Morais, V.A.; Haddad, D.; Craessaerts, K.; De Bock, P.-J.; Swerts, J.; Vilain, S.; Aerts, L.; Overbergh, L.; Grünewald, A.; Seibler, P.; et al. PINK1 Loss-of-Function Mutations Affect Mitochondrial Complex I Activity via NdufA10 Ubiquinone Uncoupling. Science 2014, 344, 203–207.
  35. Voigt, A.; Berlemann, L.A.; Winklhofer, K.F. The mitochondrial kinase PINK1: Functions beyond mitophagy. J. Neurochem. 2016, 139, 232–239.
  36. Soubannier, V.; McLelland, G.-L.; Zunino, R.; Braschi, E.; Rippstein, P.; Fon, E.A.; McBride, H.M. A Vesicular Transport Pathway Shuttles Cargo from Mitochondria to Lysosomes. Curr. Biol. 2012, 22, 135–141.
  37. Braschi, E.; Goyon, V.; Zunino, R.; Mohanty, A.; Xu, L.; McBride, H. Vps35 Mediates Vesicle Transport between the Mitochondria and Peroxisomes. Curr. Biol. 2010, 20, 1310–1315.
  38. Vilariño-Güell, C.; Wider, C.; Ross, O.; Dachsel, J.C.; Kachergus, J.M.; Lincoln, S.J.; Soto-Ortolaza, A.I.; Cobb, S.A.; Wilhoite, G.J.; Bacon, J.A.; et al. VPS35 Mutations in Parkinson Disease. Am. J. Hum. Genet. 2011, 89, 162–167.
  39. Zimprich, A.; Benet-Pagès, A.; Struhal, W.; Graf, E.; Eck, S.H.; Offman, M.N.; Haubenberger, D.; Spielberger, S.; Schulte, E.C.; Lichtner, P.; et al. A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease. Am. J. Hum. Genet. 2011, 89, 168–175.
  40. Charman, M.; Kennedy, B.E.; Osborne, N.; Karten, B. MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein. J. Lipid Res. 2010, 51, 1023–1034.
  41. Elbaz-Alon, Y.; Rosenfeld-Gur, E.; Shinder, V.; Futerman, A.; Geiger, T.; Schuldiner, M. A Dynamic Interface between Vacuoles and Mitochondria in Yeast. Dev. Cell 2014, 30, 95–102.
  42. Wong, Y.C.; Ysselstein, D.; Krainc, D. Mitochondria–lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature 2018, 554, 382–386.
  43. Demers-Lamarche, J.; Guillebaud, G.; Tlili, M.; Todkar, K.; Bélanger, N.; Grondin, M.; Nguyen, A.P.; Michel, J.; Germain, M. Loss of Mitochondrial Function Impairs Lysosomes. J. Biol. Chem. 2016, 291, 10263–10276.
  44. Todkar, K.; Chikhi, L.; Germain, M. Mitochondrial interaction with the endosomal compartment in endocytosis and mitochondrial transfer. Mitochondrion 2019, 49, 284–288.
  45. Petit, A.; Kawarai, T.; Paitel, E.; Sanjo, N.; Maj, M.; Scheid, M.; Chen, F.; Gu, Y.; Hasegawa, H.; Salehi-Rad, S.; et al. Wild-Type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-Related Mutations. J. Biol. Chem. 2005, 280, 34025–34032.
  46. Klinkenberg, M.; Thurow, N.; Gispert, S.; Ricciardi, F.; Eich, F.; Prehn, J.; Auburger, G.; Kögel, D. Enhanced vulnerability of PARK6 patient skin fibroblasts to apoptosis induced by proteasomal stress. Neuroscience 2010, 166, 422–434.
  47. Haque, M.E.; Mount, M.P.; Safarpour, F.; Abdel-Messih, E.; Callaghan, S.; Mazerolle, C.; Kitada, T.; Slack, R.; Wallace, V.; Shen, J.; et al. Inactivation of Pink1 Gene in Vivo Sensitizes Dopamine-Producing Neurons to 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and Can Be Rescued by Autosomal Recessive Parkinson Disease Genes, Parkin or DJ-1. J. Biol. Chem. 2012, 287, 23162–23170.
  48. Geisler, S.; Holmström, K.; Skujat, D.; Fiesel, F.; Rothfuss, O.C.; Kahle, P.J.; Springer, W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 2010, 12, 119–131.
  49. Bonifati, V.; Rohe, C.F.; Breedveld, G.J.; Fabrizio, E.; De Mari, M.; Tassorelli, C.; Tavella, A.; Marconi, R.; Nicholl, D.J.; Chien, H.F.; et al. Early-onset parkinsonism associated with PINK1 mutations: Frequency, genotypes, and phenotypes. Neurology 2005, 65, 87–95.
  50. Ricciardi, L.; Petrucci, S.; Guidubaldi, A.; Ialongo, T.; Serra, L.; Ferraris, A.; Spanò, B.; Bozzali, M.; Valente, E.M.; Bentivoglio, A.R. Phenotypic variability of PINK1 expression: 12 Years’ clinical follow-up of two Italian families. Mov. Disord. 2014, 29, 1561–1566.
  51. Piredda, R.; Desmarais, P.; Masellis, M.; Gasca-Salas, C. Cognitive and psychiatric symptoms in genetically determined Parkinson’s disease: A systematic review. Eur. J. Neurol. 2019, 27, 229–234.
  52. Nishioka, K.; Kefi, M.; Jasinska-Myga, B.; Wider, C.; Vilarino-Guell, C.; Ross, O.; Heckman, M.G.; Middleton, L.T.; Ishihara-Paul, L.; Gibson, R.; et al. A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 2009, 81, 391–395.
  53. Choi, J.M.; Woo, M.S.; Ma, H.-I.; Kang, S.Y.; Sung, Y.-H.; Yong, S.W.; Chung, S.J.; Kim, J.-S.; Shin, H.-W.; Lyoo, C.H.; et al. Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease. Neurogenetics 2008, 9, 263–269.
  54. Weng, Y.-H.; Chou, Y.-H.W.; Wu, W.-S.; Lin, K.-J.; Chang, H.-C.; Yen, T.-C.; Chen, R.-S.; Wey, S.-P.; Lu, C.-S. PINK1 mutation in Taiwanese early-onset parkinsonism. J. Neurol. 2007, 254, 1347–1355.
  55. Brooks, J.; Ding, J.; Sánchez, J.S.; Paisan-Ruiz, C.; Singleton, A.B.; Scholz, S. Parkin and PINK1 mutations in early-onset Parkinson’s disease: Comprehensive screening in publicly available cases and control. J. Med. Genet. 2009, 46, 375–381.
  56. Hedrich, K.; Hagenah, J.; Djarmati, A.; Hiller, A.; Lohnau, T.; Lasek, K.; Grünewald, A.; Hilker, R.; Steinlechner, S.; Boston, H.; et al. Clinical Spectrum of Homozygous and Heterozygous PINK1 Mutations in a Large German Family with Parkinson Disease. Arch. Neurol. 2006, 63, 833–838.
  57. Puschmann, A.; Fiesel, F.; Caulfield, T.R.; Hudec, R.; Ando, M.; Truban, D.; Hou, X.; Ogaki, K.; Heckman, M.G.; James, E.D.; et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain 2017, 140, 98–117.
  58. Krohn, L.; Grenn, F.P.; Makarious, M.B.; Kim, J.J.; Bandres-Ciga, S.; Roosen, D.A.; Gan-Or, Z.; Nalls, M.A.; Singleton, A.B.; Blauwendraat, C. Comprehensive assessment of PINK1 variants in Parkinson’s disease. Neurobiol. Aging 2020, 91, 168.e1–168.e5.
  59. Schneider, S.A.; Klein, C. PINK1 Type of Young-Onset Parkinson Disease. In GeneReviews®; Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J., Mirzaa, G., Amemiya, A., Eds.; University of Washington: Seattle, WA, USA, 1993.
Subjects: Allergy
Contributor :
View Times: 48
Revisions: 2 times (View History)
Update Time: 22 Nov 2021
Table of Contents


    Are you sure to Delete?

    Video Upload Options

    Do you have a full video?
    If you have any further questions, please contact Encyclopedia Editorial Office.
    Borellini, L. The Role of PINK1 in Parkinson’s Disease. Encyclopedia. Available online: (accessed on 03 July 2022).
    Borellini L. The Role of PINK1 in Parkinson’s Disease. Encyclopedia. Available at: Accessed July 03, 2022.
    Borellini, Linda. "The Role of PINK1 in Parkinson’s Disease," Encyclopedia, (accessed July 03, 2022).
    Borellini, L. (2021, November 19). The Role of PINK1 in Parkinson’s Disease. In Encyclopedia.
    Borellini, Linda. ''The Role of PINK1 in Parkinson’s Disease.'' Encyclopedia. Web. 19 November, 2021.