PINK1: One protein, multiple neuroprotective functions

Future Neurology

Volumn 4, Issue 5, 2009, Pages 575-590

  Valente, Enza Maria ^a,b   Michiorri, Silvia ^a,c   Arena, Giuseppe ^a   Gelmetti, Vania ^a  

^a CASA SOLLIEVO DELLA SOFFERENZA HOSPITAL   (Italy)

^b UNIVERSITY OF MESSINA   (Italy)

^c SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

Autophagy; Calcium; Kinase; Mitochondria; Neurodegeneration; Parkin; Parkinson's disease; PINK1

Indexed keywords

CALCIUM; MESSENGER RNA; MITOCHONDRIAL DNA; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE INDUCED PUTATIVE KINASE 1; PHOSPHOTRANSFERASE; PROTEASOME; PROTEIN PINK1; UNCLASSIFIED DRUG;

AUTOPHAGY; CLINICAL FEATURE; ENZYME ACTIVITY; GASTRULATION; HUMAN; MITOCHONDRIAL RESPIRATION; NEUROPROTECTION; NONHUMAN; PARKINSON DISEASE; PARKINSONISM; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN STRUCTURE; PROTEIN TARGETING; REVIEW; SYNAPTIC TRANSMISSION; UBIQUITINATION;

EID: 75249103450     PISSN: 14796708     EISSN: None     Source Type: Journal    
DOI: 10.2217/fnl.09.39     Document Type: Review

References (112)

1. Valente EM, Abou-Sleiman PM, Caputo V et al.: Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158-1160 (2004).
2. Albanese A, Valente EM, Romito LM et al.: The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. Neurology 64, 1958-1960 (2005).
3. Bonifati V, Rohe CF, Breedveld GJ et al.: Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology 65, 87-95 (2005).
4. Chishti MA, Bohlega S, Ahmed M et al.: T313M PINK1 mutation in an extended highly consanguineous Saudi family with early-onset Parkinson disease. Arch. Neurol. 63, 1483-1485 (2006).
5. Ibanez P, Lesage S, Lohmann E et al.: Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain 129, 686-694 (2006).
6. Ishihara-Paul L, Hulihan MM, Kachergus J et al.: PINK1 mutations and parkinsonism. Neurology 71, 896-902 (2008).
7. Kumazawa R, Tomiyama H, Li Y et al.: Mutation analysis of the PINK1 gene in 391 patients with Parkinson disease. Arch. Neurol. 65, 802-808 (2008).
8. Li Y, Tomiyama H, Sato K et al.: Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism. Neurology 64, 1955-1957 (2005).
9. Rogaeva E, Johnson J, Lang AE et al.: Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease. Arch. Neurol. 61, 1898-1904 (2004).
10. Tan EK, Yew K, Chua E et al.: PINK1 mutations in sporadic early-onset Parkinson's disease. Mov. Disord. 21, 789-793 (2006).
11. Valente EM, Salvi S, Ialongo T et al.: PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann. Neurol. 56, 336-341 (2004).
12. Klein C, Djarmati A, Hedrich K et al.: PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism. Eur. J. Hum. Genet. 13, 1086-1093 (2005).
13. Ephraty L, Porat O, Israeli D et al.: Neuropsychiatric and cognitive features in autosomal-recessive early parkinsonism due to PINK1 mutations. Mov. Disord. 22, 566-569 (2007).
14. Bentivoglio AR, Cortelli P, Valente EM et al.: Phenotypic characterisation of autosomal recessive PARK6-linked parkinsonism in three unrelated Italian families. Mov. Disord. 16, 999-1006 (2001).
15. Leutenegger AL, Salih MA, Ibanez P et al.: Juvenile-onset Parkinsonism as a result of the first mutation in the adenosine triphosphate orientation domain of PINK1. Arch. Neurol. 63, 1257-1261 (2006).
16. Gelmetti V, Ferraris A, Brusa L et al.: Late onset sporadic Parkinson's disease caused by PINK1 mutations: clinical and functional study. Mov. Disord. 23, 881-885 (2008).
17. Djarmati A, Hedrich K, Svetel M et al.: Heterozygous PINK1 mutations: a susceptibility factor for Parkinson disease? Mov. Disord. 21, 1526-1530 (2006).
18. Marongiu R, Ferraris A, Ialongo T et al.: PINK1 heterozygous rare variants: prevalence, significance and phenotypic spectrum. Hum. Mutat. 29, 565-577 (2008).
19. Toft M, Myhre R, Pielsticker L et al.: PINK1 mutation heterozygosity and the risk of Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 78, 82-84 (2007).
20. Abou-Sleiman PM, Muqit MM, McDonald NQ et al.: A heterozygous effect for PINK1 mutations in Parkinson's disease? Ann. Neurol. 60, 414-419 (2006).
21. Nakajima A, Kataoka K, Hong M et al.: BRPK, a novel protein kinase showing increased expression in mouse cancer cell lines with higher metastatic potential. Cancer Lett. 201, 195-201 (2003).
22. Unoki M, Nakamura Y: Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene 20, 4457-4465 (2001).
23. Taymans JM, Van den Haute C Baekelandt V: Distribution of PINK1 and LRRK2 in rat and mouse brain. J. Neurochem. 98, 951-961 (2006).
24. Blackinton JG, Anvret A, Beilina A et al.: Expression of PINK1 mRNA in human and rodent brain and in Parkinson's disease. Brain Res. 1184, 10-16 (2007).
25. Gandhi S, Muqit MM, Stanyer L et al.: PINK1 protein in normal human brain and Parkinson's disease. Brain 129, 1720-1731 (2006).
26. Murakami T, Moriwaki Y, Kawarabayashi T et al.: PINK1, a gene product of PARK6, accumulates in α-synucleinopathy brains. J. Neurol. Neurosurg. Psychiatry 78, 653-654 (2007).
27. Miller DW, Johnson JM, Solano SM et al.: Absence of α-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia. J. Neural Transm. 112, 1613-1624 (2005).
28. Manning G, Whyte DB, Martinez R et al.: The protein kinase complement of the human genome. Science 298, 1912-1934 (2002).
29. Silvestri L, Caputo V, Bellacchio E et al.: Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum. Mol. Genet. 14, 3477-3492 (2005).
30. Zhou C, Huang Y, Shao Y et al.: The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc. Natl Acad. Sci. USA 105, 12022-12027 (2008).
31. Beilina A, van der Bruy M, Ahmad R et al.: Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc. Natl Acad. Sci. USA 102, 5703-5708 (2005).
32. Sim CH, Lio DS, Mok SS et al.: C-terminal truncation and Parkinson's disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1. Hum. Mol. Genet. 15, 3251-3262 (2006).
33. Pridgeon JW, Olzmann JA, Chin LS et al.: PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol. 5, E172 (2007). ■ Described the first substrate of PINK1 and highlights one possible neuroprotective pathway of PINK1 against oxidative stress.
34. Clark IE, Dodson MW, Jiang C et al.: Drosophila PINK1 is required for mitochondrial function and interacts genetically with parkin. Nature 441, 1162-1166 (2006). ■■ Along with [35], these were the first to report a functional interaction between PINK1 and Parkin and their role in regulation of mitochondria dynamics.
35. Park J, Lee SB, Lee S et al.: Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441, 1157-1161 (2006). ■■ Along with [34], these were the first to report a functional interaction between PINK1 and Parkin and their role in regulation of mitochondria dynamics.
36. Kim Y, Park J, Kim S et al.: PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem. Biophys. Res. Commun. 377, 975-980 (2008). ■ First paper to demonstrate a physical interaction between PINK1 and Parkin through direct phosphorylation and the effect of Pink1 on downstream Parkin.
37. Plun-Favreau H, Klupsch K, Moisoi N et al.: The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nat. Cell Biol. 9, 1243-1252 (2007).
38. Yun J, Cao JH, Dodson MW et al.: Loss-of-function analysis suggests that Omi/HtrA2 is not an essential component of the PINK1/PARKIN pathway in vivo. J. Neurosci. 28, 14500-14510 (2008).
39. Whitworth AJ, Lee JR, Ho VM et al.: Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's disease factors Pink1 and Parkin. Dis. Model. Mech. 1, 168-174 (2008).
40. Muqit MM, Abou-Sleiman PM, Saurin AT et al.: Altered cleavage and localization of PINK1 to aggresomes in the presence of proteasomal stress. J. Neurochem. 98, 156-169 (2006).
41. Takatori S, Ito G, Iwatsubo T: Cytoplasmic localization and proteasomal degradation of N-terminally cleaved form of PINK1. Neurosci. Lett. 430, 13-17 (2008).
42. Weihofen A, Ostaszewski B, Minami Y et al.: Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and Parkin all influence the maturation or subcellular distribution of Pink1. Hum. Mol. Genet. 17, 602-616 (2008). ■ Interesting paper that dissects the fine regulation of the ratio and subcellular localization of full-length and cleaved isoforms of Pink1.
43. Lin W, Kang UJ: Characterization of PINK1 processing, stability, and subcellular localization. J. Neurochem. 106, 464-474 (2008).
44. Petit A, Kawarai T, Paitel E et al.: Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. J. Biol. Chem. 280, 34025-34032 (2005).
45. Exner N, Treske B, Paquet D et al.: Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J. Neurosci. 27, 12413-12418 (2007).
46. Weihofen A, Thomas KJ, Ostaszewski BL et al.: PINK1 forms a multiprotein complex with miro and milton, linking Pink1 function to mitochondrial trafficking. Biochemistry 48, 2045-2052 (2009).
47. Glater EE, Megeath LJ, Stowers RS et al.: Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent. J. Cell. Biol. 173, 545-557 (2006).
48. Olanow CW, Perl DP, DeMartino GN et al.: Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol. 3, 496-503 (2004).
49. Mei Y, Zhang Y, Yamamoto K et al.: FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation. Proc. Natl Acad. Sci. USA 106, 5153-5158 (2009).
50. Scheele C, Petrovic N, Faghihi MA et al.: The human PINK1 locus is regulated in vivo by a non-coding natural antisense RNA during modulation of mitochondrial function. BMC Genomics 8, 74 (2007).
51. Tang B, Xiong H, Sun P et al.: Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease. Hum. Mol. Genet. 15, 1816-1825 (2006).
52. Deng H, Jankovic J, Guo Y et al.: Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochem. Biophys. Res. Commun. 337, 1133-1138 (2005).
53. Haque ME, Thomas KJ, D'Souza C et al.: Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc. Natl Acad. Sci. USA 105, 1716-1721 (2008). ■ First paper to suggest that PINK1 could play a neuroprotective role also outside mitochondia.
54. Engelender S: Ubiquitination of α-synuclein and autophagy in Parkinson's disease. Autophagy 4, 372-374 (2008).
55. Parihar MS, Parihar A, Fujita M et al.: Mitochondrial association of α-synuclein causes oxidative stress. Cell Mol. Life Sci. 65, 1272-1284 (2008).
56. Martinez-Vicente M, Talloczy Z, Kaushik S et al.: Dopamine-modified α-synuclein blocks chaperone-mediated autophagy. J. Clin. Invest. 118, 777-788 (2008).
57. Fornai F, Lazzeri G, Bandettini Di Poggio A et al.: Convergent roles of α-synuclein, DA metabolism, and the ubiquitin-proteasome system in nigrostriatal toxicity. Ann. NY Acad. Sci. 1074, 84-89 (2006).
58. Liu W, Vives-Bauza C, Acin P et al.: PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and α-synuclein aggregation in cell culture models of Parkinson's disease. PLoS ONE 4, E4597 (2009).
59. Marongiu R, Spencer B, Crews L et al.: Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson's disease by disturbing calcium flux. J. Neurochem. 108, 1561-1574 (2009).
60. Todd AM, Staveley BE: Pink1 suppresses α-synuclein-induced phenotypes in a Drosophila model of Parkinson's disease. Genome 51, 1040-1046 (2008).
61. Haywood AF, Staveley BE: Parkin counteracts symptoms in a Drosophila model of Parkinson's disease. BMC Neurosci. 5, 14 (2004).
62. Wang D, Qian L, Xiong H et al.: Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. Proc. Natl Acad. Sci. USA 103, 13520-13525 (2006).
63. Hoepken HH, Gispert S, Morales B et al.: Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiol. Dis. 25, 401-411 (2007).
64. Hoepken HH, Gispert S, Azizov M et al.: Parkinson patient fibroblasts show increased α-synuclein expression. Exp. Neurol. 212, 307-313 (2008).
65. Schapira AH: Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 7, 97-109 (2008).
66. Morais VA, Verstreken P, Roethig A et al.: Parkinson's disease mutations in PINK1 result in decreased complex I activity and deficient synaptic function. EMBO Mol. Med. DOI:/10.1002/emmm.200900006 (2009) (Epub ahead of print).
67. Gautier CA, Kitada T, Shen J: Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc. Natl Acad. Sci. USA 105, 11364-11369 (2008). ■■ First Pink1-knockout mouse model to show abnormalities of mitochondrial respiratory chain in different brain areas.
68. Abramov AY, Canevari L, Duchen MR: Calcium signals induced by amyloid β peptide and their consequences in neurons and astrocytes in culture. Biochim. Biophys. Acta 1742, 81-87 (2004).
69. Abramov AY, Canevari L, Duchen MR: Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity. J. Neurosci. 23, 5088-5095 (2003).
70. Mattson MP: Calcium and neurodegeneration. Aging Cell 6, 337-350 (2007).
71. Martinez J, Moeller I, Erdjument-Bromage H et al.: Parkinson's disease-associated α-synuclein is a calmodulin substrate. J. Biol. Chem. 278, 17379-17387 (2003).
72. 2+ channels. Neuroreport 17, 1883-1886 (2006).
73. Danzer KM, Haasen D, Karow AR et al.: Different species of α-synuclein oligomers induce calcium influx and seeding. J. Neurosci. 27, 9220-9232 (2007).
74. Gandhi S, Wood-Kaczmar A, Yao Z et al.: PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death. Mol. Cell 33, 627-638 (2009). ■ Indicates a novel role for PINK1 in regulating intramitochondrial calcium homeostasis.
75. Detmer SA, Chan DC: Functions and dysfunctions of mitochondrial dynamics. Nat. Rev. Mol. Cell Biol. 8, 870-879 (2007).
76. Knott AB, Perkins G, Schwarzenbacher R et al.: Mitochondrial fragmentation in neurodegeneration. Nat. Rev. Neurosci. 9, 505-518 (2008).
77. Yang Y, Gehrke S, Imai Y et al.: Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc. Natl Acad. Sci. USA 103, 10793-10798 (2006).
78. Tan JM, Dawson TM: Parkin blushed by PINK1. Neuron 50, 527-529 (2006).
79. Yang Y, Ouyang Y, Yang L et al.: Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc. Natl Acad. Sci. USA 105, 7070-7075 (2008).
80. Dagda RK, Cherra SJ III, Kulich SM et al.: Loss of Pink1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J. Biol. Chem. 284, 13843-13855 (2009).
81. Park J, Lee G, Chung J: The PINK1-Parkin pathway is involved in the regulation of mitochondrial remodeling process. Biochem. Biophys. Res. Commun. 378, 518-523 (2009).
82. Levine B, Kroemer G: Autophagy in the pathogenesis of disease. Cell 132, 27-42 (2008). ■ Comprehensive review on autophagy and its multiple implications in the pathogenesis of different diseases.
83. Komatsu M, Ueno T, Waguri S et al.: Constitutive autophagy: vital role in clearance of unfavorable proteins in neurons. Cell Death Differ. 14, 887-894 (2007).
84. Martinez-Vicente M, Cuervo AM: Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol. 6, 352-361 (2007).
85. Winslow AR, Rubinsztein DC: Autophagy in neurodegeneration and development. Biochim. Biophys. Acta 1782, 723-729 (2008).
86. Kim I, Rodriguez-Enriquez S, Lemasters JJ: Selective degradation of mitochondria by mitophagy. Arch. Biochem. Biophys. 462, 245-253 (2007).
87. Narendra D, Tanaka A, Suen DF et al.: Parkin-induced mitophagy in the pathogenesis of Parkinson disease. Autophagy 5(5), 706-708 (2009).
88. Narendra D, Tanaka A, Suen DF et al.: Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell. Biol. 183, 795-803 (2008).
89. Um JW, Stichel-Gunkel C, Lubbert H et al.: Molecular interaction between parkin and PINK1 in mammalian neuronal cells. Mol. Cell Neurosci. 40, 421-432 (2009).
90. Shiba K, Arai T, Sato S et al.: Parkin stabilizes PINK1 through direct interaction. Biochem. Biophys. Res. Commun. 383, 331-335 (2009).
91. Gomes LC, Scorrano L: High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy. Biochim. Biophys. Acta 1777, 860-866 (2008).
92. Cookson MR: The biochemistry of Parkinson's disease. Annu. Rev. Biochem. 74, 29-52 (2005).
93. McNaught KS, Belizaire R, Isacson O et al.: Altered proteasomal function in sporadic Parkinson's disease. Exp. Neurol. 179, 38-46 (2003).
94. McNaught KS, Perl DP, Brownell AL et al.: Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease. Ann. Neurol. 56, 149-162 (2004).
95. Kordower JH, Kanaan NM, Chu Y et al.: Failure of proteasome inhibitor administration to provide a model of Parkinson's disease in rats and monkeys. Ann. Neurol. 60, 264-268 (2006).
96. Manning-Bog AB, Reaney SH, Chou VP et al.: Lack of nigrostriatal pathology in a rat model of proteasome inhibition. Ann. Neurol. 60, 256-260 (2006).
97. Bove J, Zhou C, Jackson-Lewis V et al.: Proteasome inhibition and Parkinson's disease modeling. Ann. Neurol. 60, 260-264 (2006).
98. Shimura H, Hattori N, Kubo S et al.: Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet. 25, 302-305 (2000).
99. Jiang H, Ren Y, Zhao J et al.: Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. Hum. Mol. Genet. 13, 1745-1754 (2004).
100. Xiong H, Wang D, Chen L et al.: Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J. Clin. Invest. 119, 650-660 (2009). ■ Describes the first function of Pink1 outside of mitochondria and its interaction with both Parkin and DJ-1.
101. 18F-dopa PET study. Ann. Neurol. 52, 849-853 (2002).
102. Kessler KR, Hamscho N, Morales B et al.: Dopaminergic function in a family with the PARK6 form of autosomal recessive Parkinson's syndrome. J. Neural Transm. 112, 1345-1353 (2005).
103. Goldberg MS, Pisani A, Haburcak M et al.: Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 45, 489-496 (2005).
104. Goldberg MS, Fleming SM, Palacino JJ et al.: Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J. Biol. Chem. 278, 43628-43635 (2003).
105. Kitada T, Pisani A, Porter DR et al.: Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc. Natl Acad. Sci. USA 104, 11441-11446 (2007).
106. Martella G, Platania P, Vita D et al.: Enhanced sensitivity to group II mGlu receptor activation at corticostriatal synapses in mice lacking the familial parkinsonism-linked genes PINK1 or Parkin. Exp. Neurol. 215, 388-396 (2009).
107. Zhou H, Falkenburger BH, Schulz JB et al.: Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in mice. Int. J. Biol. Sci. 3, 242-250 (2007).
108. Poole AC, Thomas RE, Andrews LA et al.: The PINK1/Parkin pathway regulates mitochondrial morphology. Proc. Natl Acad. Sci. USA 105, 1638-1643 (2008).
109. Anichtchik O, Diekmann H, Fleming A et al.: Loss of PINK1 function affects development and results in neurodegeneration in zebrafish. J. Neurosci. 28, 8199-8207 (2008).
110. Petko JA, Kabbani N, Frey C et al.: Proteomic and functional analysis of NCS-1 binding proteins reveals novel signaling pathways required for inner ear development in zebrafish. BMC Neurosci. 10, 27 (2009).
111. Deng H, Dodson MW, Huang H et al.: The Parkinson's disease genes PINK1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc. Natl Acad. Sci. USA 105, 14503-14508 (2008).
112. Samann J, Hegermann J, Gromoff EV et al.: Caenorhabditis elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. J. Biol. Chem. 284, 16482-16491 (2009).