Defective Autophagy in Parkinson’s Disease: Lessons from Genetics

Molecular Neurobiology

Volumn 51, Issue 1, 2015, Pages 89-104

  Zhang, H ^a   Duan, C ^a   Yang, H ^a  

^a CAPITAL MEDICAL UNIVERSITY   (China)

Author keywords

Autophagy; Parkin; Parkinson s disease; PINK1; Synuclein

Indexed keywords

ALPHA SYNUCLEIN;

ANIMAL; AUTOPHAGY; BIOLOGICAL MODEL; GENETICS; HUMAN; LYSOSOME; METABOLISM; MITOPHAGY; PARKINSON DISEASE; PATHOLOGY; PATHOPHYSIOLOGY;

ALPHA-SYNUCLEIN; ANIMALS; AUTOPHAGY; HUMANS; LYSOSOMES; MITOCHONDRIAL DEGRADATION; MODELS, BIOLOGICAL; PARKINSON DISEASE;

EID: 84930668368     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-014-8787-5     Document Type: Review

References (179)

1. Klingelhoefer L, Reichmann H (2014) Dementia—the real problem for patients with Parkinson’s disease. Basal Ganglia. doi:10.1016/j.baga.2014.03.003
2. Heller J, Dogan I, Schulz JB, Reetz K (2014) Evidence for gender differences in cognition, emotion and quality of life in Parkinson’s disease? Aging Dis 5(1):63–75. doi:10.14366/AD.2014.050063
3. Reeve AK, Park TK, Jaros E, Campbell GR, Lax NZ, Hepplewhite PD, Krishnan KJ, Elson JL, Morris CM, McKeith IG, Turnbull DM (2012) Relationship between mitochondria and alpha-synuclein: a study of single substantia nigra neurons. Arch Neurol 69(3):385–393. doi:10.1001/archneurol.2011.2675
4. Cheung ZH, Ip NY (2009) The emerging role of autophagy in Parkinson’s disease. Mol Brain 2:29. doi:10.1186/1756-6606-2-29
5. Lin TK, Chen SD, Chuang YC, Lin HY, Huang CR, Chuang JH, Wang PW, Huang ST, Tiao MM, Chen JB, Liou CW (2014) Resveratrol partially prevents rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through induction of heme oxygenase-1 dependent autophagy. Int J Mol Sci 15(1):1625–1646. doi:10.3390/ijms15011625
6. Cheung ZH, Ip NY (2011) Autophagy deregulation in neurodegenerative diseases—recent advances and future perspectives. J Neurochem 118(3):317–325. doi:10.1111/j.1471-4159.2011.07314.x
7. Lynch-Day MA, Mao K, Wang K, Zhao M, Klionsky DJ (2012) The role of autophagy in Parkinson’s disease. Cold Spring Harb Perspect Med 2(4):a009357. doi:10.1101/cshperspect.a009357
8. Bove J, Martinez-Vicente M, Dehay B, Perier C, Recasens A, Bombrun A, Antonsson B, Vila M (2014) BAX channel activity mediates lysosomal disruption linked to Parkinson disease. Autophagy 10(5)
9. Metcalf DJ, Garcia-Arencibia M, Hochfeld WE, Rubinsztein DC (2012) Autophagy and misfolded proteins in neurodegeneration. Exp Neurol 238(1):22–28. doi:10.1016/j.expneurol.2010.11.003
10. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–889. doi:10.1038/nature04724
11. Anglade P, Vyas S, JavoyAgid F, Herrero MT, Michel PP, Marquez J, MouattPrigent A, Ruberg M, Hirsch EC, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12(1):25–31
12. Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci 29(43):13578–13588. doi:10.1523/JNEUROSCI.4390-09.2009
13. Song JX, Lu JH, Liu LF, Chen LL, Durairajan SS, Yue Z, Zhang HQ, Li M (2014) HMGB1 is involved in autophagy inhibition caused by SNCA/alpha-synuclein overexpression: a process modulated by the natural autophagy inducer corynoxine B. Autophagy 10(1):144–154. doi:10.4161/auto.26751
14. Xiong N, Xiong J, Jia M, Liu L, Zhang X, Chen Z, Huang J, Zhang Z, Hou L, Luo Z, Ghoorah D, Lin Z, Wang T (2013) The role of autophagy in Parkinson’s disease: rotenone-based modeling. Behav Brain Funct 9:13. doi:10.1186/1744-9081-9-13
15. Bae EJ, Lee HJ, Jang YH, Michael S, Masliah E, Min DS, Lee SJ (2014) Phospholipase D1 regulates autophagic flux and clearance of alpha-synuclein aggregates. Cell Death Differ. doi:10.1038/cdd.2014.30
16. Reggiori F, Klionsky DJ (2013) Autophagic processes in yeast: mechanism, machinery and regulation. Genetics 194(2):341–361. doi:10.1534/genetics.112.149013
17. Feng Y, He D, Yao Z, Klionsky DJ (2014) The machinery of macroautophagy. Cell Res 24(1):24–41. doi:10.1038/cr.2013.168
18. Green DR, Levine B (2014) To be or not to be? How selective autophagy and cell death govern cell fate. Cell 157(1):65–75. doi:10.1016/j.cell.2014.02.049
19. Hale AN, Ledbetter DJ, Gawriluk TR, Rucker EB 3rd (2013) Autophagy: regulation and role in development. Autophagy 9(7):951–972. doi:10.4161/auto.24273
20. Tukaj C (2013) The significance of macroautophagy in health and disease. Folia Morphol (Warsz) 72(2):87–93. doi:10.5603/fm.2013.0015
21. Ashrafi G, Schwarz TL (2013) The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ 20(1):31–42. doi:10.1038/cdd.2012.81
22. Li WW, Li J, Bao JK (2012) Microautophagy: lesser-known self-eating. Cell Mol Life Sci 69(7):1125–1136. doi:10.1007/s00018-011-0865-5
23. Chong ZZ, Shang YC, Wang S, Maiese K (2012) Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin. Prog Neurobiol 99(2):128–148. doi:10.1016/j.pneurobio.2012.08.001
24. Stefanis L (2012) Alpha-synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med 2(2):a009399. doi:10.1101/cshperspect.a009399
25. Arias E, Cuervo AM (2011) Chaperone-mediated autophagy in protein quality control. Curr Opin Cell Biol 23(2):184–189. doi:10.1016/j.ceb.2010.10.009
26. Koga H, Cuervo AM (2011) Chaperone-mediated autophagy dysfunction in the pathogenesis of neurodegeneration. Neurobiol Dis 43(1):29–37. doi:10.1016/j.nbd.2010.07.006
27. Kaushik S, Cuervo AM (2012) Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol 22(8):407–417. doi:10.1016/j.tcb.2012.05.006
28. Fan X, Jin WY, Lu J, Wang J, Wang YT (2014) Rapid and reversible knockdown of endogenous proteins by peptide-directed lysosomal degradation. Nat Neurosci 17(3):471–480. doi:10.1038/nn.3637
29. Fred Dice J (1990) Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci 15(8):305–309
30. Li B, Zhang Y, Yuan Y, Chen N (2011) A new perspective in Parkinson’s disease, chaperone-mediated autophagy. Parkinsonism Relat Disord 17(4):231–235. doi:10.1016/j.parkreldis.2010.12.008
31. Alvarez-Erviti L, Rodriguez-Oroz MC, Cooper JM, Caballero C, Ferrer I, Obeso JA, Schapira AH (2010) Chaperone-mediated autophagy markers in Parkinson disease brains. Arch Neurol 67(12):1464–1472. doi:10.1001/archneurol.2010.198
32. Cuervo AM (2010) Chaperone-mediated autophagy: selectivity pays off. Trends Endocrinol Metab 21(3):142–150. doi:10.1016/j.tem.2009.10.003
33. Xilouri M, Brekk OR, Landeck N, Pitychoutis PM, Papasilekas T, Papadopoulou-Daifoti Z, Kirik D, Stefanis L (2013) Boosting chaperone-mediated autophagy in vivo mitigates alpha-synuclein-induced neurodegeneration. Brain 136(Pt 7):2130–2146. doi:10.1093/brain/awt131
34. Xilouri M, Brekk OR, Kirik D, Stefanis L (2013) LAMP2A as a therapeutic target in Parkinson disease. Autophagy 9(12):2166–2168. doi:10.4161/auto.26451
35. Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L (2009) Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One 4(5):e5515. doi:10.1371/journal.pone.0005515
36. Illes-Toth E, Dalton CF, Smith DP (2013) Binding of dopamine to alpha-synuclein is mediated by specific conformational states. J Am Soc Mass Spectrom 24(9):1346–1354. doi:10.1007/s13361-013-0676-z
37. Munoz P, Huenchuguala S, Paris I, Segura-Aguilar J (2012) Dopamine oxidation and autophagy. Park Dis 2012:920953. doi:10.1155/2012/920953
38. Leong SL, Pham CL, Galatis D, Fodero-Tavoletti MT, Perez K, Hill AF, Masters CL, Ali FE, Barnham KJ, Cappai R (2009) Formation of dopamine-mediated alpha-synuclein-soluble oligomers requires methionine oxidation. Free Radic Biol Med 46(10):1328–1337. doi:10.1016/j.freeradbiomed.2009.02.009
39. Nakaso K, Tajima N, Ito S, Teraoka M, Yamashita A, Horikoshi Y, Kikuchi D, Mochida S, Nakashima K, Matsura T (2013) Dopamine-mediated oxidation of methionine 127 in alpha-synuclein causes cytotoxicity and oligomerization of alpha-synuclein. PLoS One 8(2):e55068. doi:10.1371/journal.pone.0055068
40. Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D, Cuervo AM (2008) Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest 118(2):777–788. doi:10.1172/JCI32806
41. Xilouri M, Brekk OR, Stefanis L (2012) Alpha-synuclein and protein degradation systems: a reciprocal relationship. Mol Neurobiol 47(2):537–551. doi:10.1007/s12035-012-8341-2
42. Yang Q, Mao Z (2010) Dysregulation of autophagy and Parkinson’s disease: the MEF2D link. Apoptosis 15(11):1410–1414. doi:10.1007/s10495-010-0475-y
43. Dietrich JB (2013) The MEF2 family and the brain: from molecules to memory. Cell Tissue Res 352(2):179–190. doi:10.1007/s00441-013-1565-2
44. Gao L, She H, Li W, Zeng J, Zhu J, Jones DP, Mao Z, Gao G, Yang Q (2014) Oxidation of survival factor MEF2D in neuronal death and Parkinson’s disease. Antioxid Redox Signal. doi:10.1089/ars.2013.5399
45. Yang Q, She H, Gearing M, Colla E, Lee M, Shacka JJ, Mao Z (2009) Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science 323(5910):124–127. doi:10.1126/science.1166088
46. Alvarez-Erviti L, Seow Y, Schapira AH, Rodriguez-Oroz MC, Obeso JA, Cooper JM (2013) Influence of microRNA deregulation on chaperone-mediated autophagy and alpha-synuclein pathology in Parkinson’s disease. Cell Death Dis 4:e545. doi:10.1038/cddis.2013.73
47. Cuervo AM, Wong E (2014) Chaperone-mediated autophagy: roles in disease and aging. Cell Res 24(1):92–104. doi:10.1038/cr.2013.153
48. Rubinsztein DC, Shpilka T, Elazar Z (2012) Mechanisms of autophagosome biogenesis. Curr Biol 22(1):R29–R34. doi:10.1016/j.cub.2011.11.034
49. Tanik SA, Schultheiss CE, Volpicelli-Daley LA, Brunden KR, Lee VM (2013) Lewy body-like alpha-synuclein aggregates resist degradation and impair macroautophagy. J Biol Chem 288(21):15194–15210. doi:10.1074/jbc.M113.457408
50. Winslow AR, Rubinsztein DC (2011) The Parkinson disease protein alpha-synuclein inhibits autophagy. Autophagy 7(4):429–431
51. Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE, Peden AA, Lichtenberg M, Menzies FM, Ravikumar B, Imarisio S, Brown S, O’Kane CJ, Rubinsztein DC (2010) Alpha-synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol 190(6):1023–1037. doi:10.1083/jcb.201003122
52. Li L, Nadanaciva S, Berger Z, Shen W, Paumier K, Schwartz J, Mou K, Loos P, Milici AJ, Dunlop J, Hirst WD (2013) Human A53T alpha-synuclein causes reversible deficits in mitochondrial function and dynamics in primary mouse cortical neurons. PLoS One 8(12):e85815. doi:10.1371/journal.pone.0085815
53. Massey AC, Kaushik S, Sovak G, Kiffin R, Cuervo AM (2006) Consequences of the selective blockage of chaperone-mediated autophagy. Proc Natl Acad Sci U S A 103(15):5805–5810. doi:10.1073/pnas.0507436103
54. Marta Martinez-Vicente ZT, Kaushik S, Massey AC (2008) Dopamine-modified α-synuclein blocks chaperone-mediated autophagy. J Clin Invest 118(2). doi:10.1172/jci32806ds1
55. Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P (2009) Alpha-synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells. Int J Biochem Cell Biol 41(10):2015–2024. doi:10.1016/j.biocel.2009.05.008
56. Xie W, Chung KKK (2012) Alpha-synuclein impairs normal dynamics of mitochondria in cell and animal models of Parkinson’s disease. J Neurochem 122(2):404–414. doi:10.1111/j.1471-4159.2012.07769.x
57. Shavali S, Brown-Borg HM, Ebadi M, Porter J (2008) Mitochondrial localization of alpha-synuclein protein in alpha-synuclein overexpressing cells. Neurosci Lett 439(2):125–128. doi:10.1016/j.neulet.2008.05.005
58. Zhu Y, Duan C, Lu L, Gao H, Zhao C, Yu S, Ueda K, Chan P, Yang H (2011) Alpha-synuclein overexpression impairs mitochondrial function by associating with adenylate translocator. Int J Biochem Cell Biol 43(5):732–741. doi:10.1016/j.biocel.2011.01.014
59. Lu L, Zhang C, Cai Q, Lu Q, Duan C, Zhu Y, Yang H (2013) Voltage-dependent anion channel involved in the alpha-synuclein-induced dopaminergic neuron toxicity in rats. Acta Biochim Biophys Sin (Shanghai) 45(3):170–178. doi:10.1093/abbs/gms114
60. Chinta SJ, Mallajosyula JK, Rane A, Andersen JK (2010) Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci Lett 486(3):235–239. doi:10.1016/j.neulet.2010.09.061
61. Wager K, Russell C (2013) Mitophagy and neurodegeneration: the zebrafish model system. Autophagy 9(11):1693–1709. doi:10.4161/auto.25082
62. Matsui H, Gavinio R, Asano T, Uemura N, Ito H, Taniguchi Y, Kobayashi Y, Maki T, Shen J, Takeda S, Uemura K, Yamakado H, Takahashi R (2013) PINK1 and Parkin complementarily protect dopaminergic neurons in vertebrates. Hum Mol Genet 22(12):2423–2434. doi:10.1093/hmg/ddt095
63. Jin SM, Youle RJ (2012) PINK1- and Parkin-mediated mitophagy at a glance. J Cell Sci 125(4):795–799. doi:10.1242/Jcs.093849
64. Exner N, Lutz AK, Haass C, Winklhofer KF (2012) Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J 31(14):3038–3062. doi:10.1038/emboj.2012.170
65. Kato H, Lu Q, Rapaport D, Kozjak-Pavlovic V (2013) Tom70 is essential for PINK1 import into mitochondria. PLoS One 8(3):e58435. doi:10.1371/journal.pone.0058435
66. Lu G, Ren S, Korge P, Choi J, Dong Y, Weiss J, Koehler C, Chen JN, Wang Y (2007) A novel mitochondrial matrix serine/threonine protein phosphatase regulates the mitochondria permeability transition pore and is essential for cellular survival and development. Genes Dev 21(7):784–796. doi:10.1101/gad.1499107
67. Gomez-Sanchez R, Gegg ME, Bravo-San Pedro JM, Niso-Santano M, Alvarez-Erviti L, Pizarro-Estrella E, Gutierrez-Martin Y, Alvarez-Barrientos A, Fuentes JM, Gonzalez-Polo RA, Schapira AH (2014) Mitochondrial impairment increases FL-PINK1 levels by calcium-dependent gene expression. Neurobiol Dis 62:426–440. doi:10.1016/j.nbd.2013.10.021
68. Moisoi N, Fedele V, Edwards J, Martins LM (2014) Loss of PINK1 enhances neurodegeneration in a mouse model of Parkinson’s disease triggered by mitochondrial stress. Neuropharmacology 77:350–357. doi:10.1016/j.neuropharm.2013.10.009
69. Kawajiri S, Saiki S, Sato S, Hattori N (2011) Genetic mutations and functions of PINK1. Trends Pharmacol Sci 32(10):573–580. doi:10.1016/j.tips.2011.06.001
70. Dagda RK, Cherra SJ 3rd, Kulich SM, Tandon A, Park D, Chu CT (2009) Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 284(20):13843–13855. doi:10.1074/jbc.M808515200
71. Gandhi S, Wood-Kaczmar A, Yao Z, Plun-Favreau H, Deas E, Klupsch K, Downward J, Latchman DS, Tabrizi SJ, Wood NW, Duchen MR, Abramov AY (2009) PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 33(5):627–638. doi:10.1016/j.molcel.2009.02.013
72. Wang HL, Chou AH, Wu AS, Chen SY, Weng YH, Kao YC, Yeh TH, Chu PJ, Lu CS (2011) PARK6 PINK1 mutants are defective in maintaining mitochondrial membrane potential and inhibiting ROS formation of substantia nigra dopaminergic neurons. Biochim Biophys Acta 1812(6):674–684. doi:10.1016/j.bbadis.2011.03.007
73. Akundi RS, Zhi L, Sullivan PG, Büeler H (2012) Shared and cell type-specific mitochondrial defects and metabolic adaptations in primary cells from PINK1-deficient mice. Neurodegener Dis. doi:10.1159/000345689
74. Esposito G, Vos M, Vilain S, Swerts J, De Sousa Valadas J, Van Meensel S, Schaap O, Verstreken P (2013) Aconitase causes iron toxicity in Drosophila pink1 mutants. PLoS Genet 9(4):e1003478. doi:10.1371/journal.pgen.1003478
75. Pridgeon JW, Olzmann JA, Chin LS, Li L (2007) PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1. PLoS Biol 5(7):e172. doi:10.1371/journal.pbio.0050172
76. Costa AC, Loh SH, Martins LM (2013) Drosophila Trap1 protects against mitochondrial dysfunction in a PINK1/parkin model of Parkinson’s disease. Cell Death Dis 4:e467. doi:10.1038/cddis.2012.205
77. Cui T, Fan C, Gu L, Gao H, Liu Q, Zhang T, Qi Z, Zhao C, Zhao H, Cai Q, Yang H (2011) Silencing of PINK1 induces mitophagy via mitochondrial permeability transition in dopaminergic MN9D cells. Brain Res 1394:1–13. doi:10.1016/j.brainres.2011.01.035
78. Qi Z, Yang W, Liu Y, Cui T, Gao H, Duan C, Lu L, Zhao C, Zhao H, Yang H (2011) Loss of PINK1 function decreases PP2A activity and promotes autophagy in dopaminergic cells and a murine model. Neurochem Int 59(5):572–581. doi:10.1016/j.neuint.2011.03.023
79. de Vries RL, Przedborski S (2013) Mitophagy and Parkinson’s disease: be eaten to stay healthy. Mol Cell Neurosci 55:37–43. doi:10.1016/j.mcn.2012.07.008
80. Vincowa ES, Merrihew G, Thomas RE, Shulman NJ, Beyer RP, MacCoss MJ, Pallanck LJ (2013) The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc Natl Acad Sci U S A 110(16):6400–6405
81. Spratt DE, Martinez-Torres RJ, Noh YJ, Mercier P, Manczyk N, Barber KR, Aguirre JD, Burchell L, Purkiss A, Walden H, Shaw GS (2013) A molecular explanation for the recessive nature of parkin-linked Parkinson’s disease. Nat Commun 4:1983. doi:10.1038/ncomms2983
82. Vercammen L, Van der Perren A, Vaudano E, Gijsbers R, Debyser Z, Van den Haute C, Baekelandt V (2006) Parkin protects against neurotoxicity in the 6-hydroxydopamine rat model for Parkinson’s disease. Mol Ther 14(5):716–723. doi:10.1016/j.ymthe.2006.06.009
83. Winklhofer KF (2007) The parkin protein as a therapeutic target in Parkinson’s disease. Expert Opin Ther Targets 11(12):1543–1552
84. Fett ME, Pilsl A, Paquet D, van Bebber F, Haass C, Tatzelt J, Schmid B, Winklhofer KF (2010) Parkin is protective against proteotoxic stress in a transgenic zebrafish model. PLoS One 5(7). doi:10.1371/journal.pone.0011783
85. Cali T, Ottolini D, Negro A, Brini M (2013) Enhanced parkin levels favor ER-mitochondria crosstalk and guarantee Ca(2+) transfer to sustain cell bioenergetics. Biochim Biophys Acta 1832(4):495–508. doi:10.1016/j.bbadis.2013.01.004
86. Haskin J, Szargel R, Shani V, Mekies LN, Rott R, Lim GGY, Lim KL, Bandopadhyay R, Wolosker H, Engelender S (2013) AF-6 is a positive modulator of the PINK1/parkin pathway and is deficient in Parkinson’s disease. Hum Mol Genet 22(10):2083–2096. doi:10.1093/Hmg/Ddt058
87. Lonskaya I, Hebron ML, Algarzae NK, Desforges N, Moussa CE (2012) Decreased parkin solubility is associated with impairment of autophagy in the nigrostriatum of sporadic Parkinson’s disease. Neuroscience 232C:90. doi:10.1016/j.neuroscience.2012.12.018
88. Higgins GC, Coughlan MT (2014) Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy? Br J Pharmacol 171(8):1917–1942. doi:10.1111/bph.12503
89. Cordero MD, De Miguel M, Moreno Fernandez AM, Carmona Lopez IM, Garrido Maraver J, Cotan D, Gomez Izquierdo L, Bonal P, Campa F, Bullon P, Navas P, Sanchez Alcazar JA (2010) Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease. Arthritis Res Ther 12(1):R17. doi:10.1186/ar2918
90. Perier C, Vila M (2012) Mitochondrial biology and Parkinson’s disease. Cold Spring Harb Perspect Med 2(2):a009332. doi:10.1101/cshperspect.a009332
91. Geisler S, Holmstrom KM, Treis A, Skujat D, Weber SS, Fiesel FC, Kahle PJ, Springer W (2010) The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 6(7):871–878. doi:10.4161/auto.6.7.13286
92. Seibler P, Graziotto J, Jeong H, Simunovic F, Klein C, Krainc D (2011) Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J Neurosci 31(16):5970–5976. doi:10.1523/jneurosci.4441-10.2011
93. Cherra SJ, Dagda RK, Tandon A, Chu CT (2009) Mitochondrial autophagy as a compensatory response to PINK1 deficiency. Autophagy 5(8):1213–1214
94. Koyano F, Okatsu K, Ishigaki S, Fujioka Y, Kimura M, Sobue G, Tanaka K, Matsuda N (2013) The principal PINK1 and Parkin cellular events triggered in response to dissipation of mitochondrial membrane potential occur in primary neurons. Genes Cells 18(8):672–681. doi:10.1111/gtc.12066
95. Zhou C, Huang Y, Shao Y, May J, Prou D, Perier C, Dauer W, Schon EA, Przedborski S (2008) The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc Natl Acad Sci U S A 105(33):12022–12027. doi:10.1073/pnas.0802814105
96. Kim Y, Park J, Kim S, Song S, Kwon S-K, Lee S-H, Kitada T, Kim J-M, Chung J (2008) PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun 377(3):975–980. doi:10.1016/j.bbrc.2008.10.104
97. Ziviani E, Tao RN, Whitworth AJ (2010) Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin. Proc Natl Acad Sci U S A 107(11):5018–5023. doi:10.1073/pnas.0913485107
98. Okatsu K, Uno M, Koyano F, Go E, Kimura M, Oka T, Tanaka K, Matsuda N (2013) A dimeric PINK1-containing complex on depolarized mitochondria stimulates Parkin recruitment. J Biol Chem 288(51):36372–36384. doi:10.1074/jbc.M113.509653
99. Iguchi M, Kujuro Y, Okatsu K, Koyano F, Kosako H, Kimura M, Suzuki N, Uchiyama S, Tanaka K, Matsuda N (2013) Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent phosphorylation. J Biol Chem 288(30):22019–22032
100. Sun Y, Vashisht AA, Tchieu J, Wohlschlegel JA, Dreier L (2012) Voltage-dependent anion channels (VDACs) recruit Parkin to defective mitochondria to promote mitochondrial autophagy. J Biol Chem 287(48):40652–40660. doi:10.1074/jbc.M112.419721
101. Feng D, Liu L, Zhu Y, Chen Q (2013) Molecular signaling toward mitophagy and its physiological significance. Exp Cell Res 319(12):1697–1705. doi:10.1016/j.yexcr.2013.03.034
102. Bertolin G, Ferrando-Miguel R, Jacoupy M, Traver S, Grenier K, Greene AW, Dauphin A, Waharte F, Bayot A, Salamero J, Lombes A, Bulteau AL, Fon EA, Brice A, Corti O (2013) The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance. Autophagy 9(11):1801–1817. doi:10.4161/auto.25884
103. Rana A, Rera M, Walker DW (2013) Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proc Natl Acad Sci U S A 110(21):8638–8643. doi:10.1073/pnas.1216197110
104. Chen Y, Dorn GW 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340(6131):471–475. doi:10.1126/science.1231031
105. Malkus KA, Tsika E, Ischiropoulos H (2009) Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson’s disease: how neurons are lost in the Bermuda triangle. Mol Neurodegener 4:24. doi:10.1186/1750-1326-4-24
106. Wang H, Song P, Du L, Tian W, Yue W, Liu M, Li D, Wang B, Zhu Y, Cao C, Zhou J, Chen Q (2011) Parkin ubiquitinates Drp1 for proteasome-dependent degradation: implication of dysregulated mitochondrial dynamics in Parkinson disease. J Biol Chem 286(13):11649–11658. doi:10.1074/jbc.M110.144238
107. Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, Tyurin VA, Yanamala N, Shrivastava IH, Mohammadyani D, Qiang Wang KZ, Zhu J, Klein-Seetharaman J, Balasubramanian K, Amoscato AA, Borisenko G, Huang Z, Gusdon AM, Cheikhi A, Steer EK, Wang R, Baty C, Watkins S, Bahar I, Bayir H, Kagan VE (2013) Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol 15(10):1197–1205. doi:10.1038/ncb2837
108. Chu CT, Bayir H, Kagan VE (2014) LC3 binds externalized cardiolipin on injured mitochondria to signal mitophagy in neurons: implications for Parkinson disease. Autophagy 10(2):376–378. doi:10.4161/auto.27191
109. Cook KL, Soto-Pantoja D, Abu-Asab M, Clarke PA, Roberts DD, Clarke R (2014) Mitochondria directly donate their membrane to form autophagosomes during a novel mechanism of parkin-associated mitophagy. Cell Biosci 4(1):16
110. Zhao T, Severijnen LA, van der Weiden M, Zheng PP, Oostra BA, Hukema RK, Willemsen R, Kros JM, Bonifati V (2013) FBXO7 immunoreactivity in alpha-synuclein-containing inclusions in Parkinson disease and multiple system atrophy. J Neuropathol Exp Neurol 72(6):482–488. doi:10.1097/NEN.0b013e318293c586
111. Burchell VS, Nelson DE, Sanchez-Martinez A, Delgado-Camprubi M, Ivatt RM, Pogson JH, Randle SJ, Wray S, Lewis PA, Houlden H, Abramov AY, Hardy J, Wood NW, Whitworth AJ, Laman H, Plun-Favreau H (2013) The Parkinson’s disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy. Nat Neurosci. doi:10.1038/nn.3489
112. Settembre C, Fraldi A, Medina DL, Ballabio A (2013) Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol 14(5):283–296. doi:10.1038/nrm3565
113. Dehay B, Bove J, Rodriguez-Muela N, Perier C, Recasens A, Boya P, Vila M (2010) Pathogenic lysosomal depletion in Parkinson’s disease. J Neurosci 30(37):12535–12544. doi:10.1523/JNEUROSCI.1920-10.2010
114. Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordower JH (2009) Alterations in lysosomal and proteasomal markers in Parkinson’s disease: relationship to alpha-synuclein inclusions. Neurobiol Dis 35(3):385–398. doi:10.1016/j.nbd.2009.05.023
115. Blech-Hermoni YN, Ziegler SG, Hruska KS, Stubblefield BK, Lamarca ME, Portnoy ME, Program NCS, Green ED, Sidransky E (2010) In silico and functional studies of the regulation of the glucocerebrosidase gene. Mol Genet Metab 99(3):275–282. doi:10.1016/j.ymgme.2009.10.189
116. Osellame LD, Duchen MR (2013) Defective quality control mechanisms and accumulation of damaged mitochondria link Gaucher and Parkinson diseases. Autophagy 9(10):1633–1635. doi:10.4161/auto.25878
117. Cleeter MW, Chau KY, Gluck C, Mehta A, Hughes DA, Duchen M, Wood NW, Hardy J, Mark Cooper J, Schapira AH (2013) Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage. Neurochem Int 62(1):1–7. doi:10.1016/j.neuint.2012.10.010
118. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, Sidransky E, Grabowski GA, Krainc D (2011) Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146(1):37–52. doi:10.1016/j.cell.2011.06.001
119. Ginns EI, Mak SK, Ko N, Karlgren J, Akbarian S, Chou VP, Guo Y, Lim A, Samuelsson S, LaMarca ML, Vazquez-DeRose J, Manning-Bog AB (2014) Neuroinflammation and alpha-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction. Mol Genet Metab 111(2):152–162. doi:10.1016/j.ymgme.2013.12.003
120. Westbroek W, Gustafson AM, Sidransky E (2011) Exploring the link between glucocerebrosidase mutations and parkinsonism. Trends Mol Med 17(9):485–493. doi:10.1016/j.molmed.2011.05.003
121. Dehay B, Martinez-Vicente M, Caldwell GA, Caldwell KA, Yue Z, Cookson MR, Klein C, Vila M, Bezard E (2013) Lysosomal impairment in Parkinson’s disease. Mov Disord 28(6):725–732. doi:10.1002/mds.25462
122. Dehay B, Ramirez A, Martinez-Vicente M, Perier C, Canron MH, Doudnikoff E, Vital A, Vila M, Klein C, Bezard E (2012) Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc Natl Acad Sci U S A 109(24):9611–9616. doi:10.1073/pnas.1112368109
123. Murphy KE, Cottle L, Gysbers AM, Cooper AA, Halliday GM (2013) ATP13A2 (PARK9) protein levels are reduced in brain tissue of cases with Lewy bodies. Acta Neuropathol Commun 1(1):11. doi:10.1186/2051-5960-1-11
124. Usenovic M, Knight AL, Ray A, Wong V, Brown KR, Caldwell GA, Caldwell KA, Stagljar I, Krainc D (2012) Identification of novel ATP13A2 interactors and their role in alpha-synuclein misfolding and toxicity. Hum Mol Genet 21(17):3785–3794. doi:10.1093/hmg/dds206
125. Kong SM, Chan BK, Park JS, Hill KJ, Aitken JB, Cottle L, Farghaian H, Cole AR, Lay PA, Sue CM, Cooper AA (2014) Parkinson’s disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes alpha-synuclein externalization via exosomes. Hum Mol Genet. doi:10.1093/hmg/ddu099
126. Gusdon AM, Zhu J, Van Houten B, Chu CT (2012) ATP13A2 regulates mitochondrial bioenergetics through macroautophagy. Neurobiol Dis 45(3):962–972. doi:10.1016/j.nbd.2011.12.015
127. Usenovic M, Tresse E, Mazzulli JR, Taylor JP, Krainc D (2012) Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha-synuclein accumulation, and neurotoxicity. J Neurosci 32(12):4240–4246. doi:10.1523/JNEUROSCI.5575-11.2012
128. Tofaris GK (2012) Lysosome-dependent pathways as a unifying theme in Parkinson’s disease. Mov Disord 27(11):1364–1369. doi:10.1002/mds.25136
129. Park JS, Koentjoro B, Veivers D, Mackay-Sim A, Sue CM (2014) Parkinson’s disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction. Hum Mol Genet. doi:10.1093/hmg/ddt623
130. Dehay B, Martinez-Vicente M, Ramirez A, Perier C, Klein C, Vila M, Bezard E (2012) Lysosomal dysfunction in Parkinson disease: ATP13A2 gets into the groove. Autophagy 8(9):1389–1391. doi:10.4161/auto.21011
131. Scarffe LA, Stevens DA, Dawson VL, Dawson TM (2014) Parkin and PINK1: much more than mitophagy. Trends Neurosci. doi:10.1016/j.tins.2014.03.004
132. Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA (2006) LRRK2 in Parkinson’s disease: protein domains and functional insights. Trends Neurosci 29(5):286–293. doi:10.1016/j.tins.2006.03.006
133. Manzoni C, Mamais A, Dihanich S, McGoldrick P, Devine MJ, Zerle J, Kara E, Taanman JW, Healy DG, Marti-Masso JF, Schapira AH, Plun-Favreau H, Tooze S, Hardy J, Bandopadhyay R, Lewis PA (2013) Pathogenic Parkinson’s disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation. Biochem Biophys Res Commun 441(4):862–866. doi:10.1016/j.bbrc.2013.10.159
134. Dorval V, Mandemakers W, Jolivette F, Coudert L, Mazroui R, De Strooper B, Hebert SS (2014) Gene and MicroRNA transcriptome analysis of Parkinson’s related LRRK2 mouse models. PLoS One 9(1):e85510. doi:10.1371/journal.pone.0085510
135. Wang G, Pan J, Chen SD (2012) Kinases and kinase signaling pathways: potential therapeutic targets in Parkinson’s disease. Prog Neurobiol 98(2):207–221. doi:10.1016/j.pneurobio.2012.06.003
136. Su YC, Qi X (2013) Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet. doi:10.1093/hmg/ddt301
137. Yue ZY, Yang XW (2013) Dangerous duet: LRRK2 and alpha-synuclein jam at CMA. Nat Neurosci 16(4):375–377. doi:10.1038/Nn.3361
138. Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig LS, Dauer W, Consiglio A, Raya A, Sulzer D, Cuervo AM (2013) Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci 16(4):394–U352. doi:10.1038/Nn.3350
139. Sanchez-Perez AM, Claramonte-Clausell B, Sanchez-Andres JV, Herrero MT (2012) Parkinson’s disease and autophagy. Park Dis 2012:429524. doi:10.1155/2012/429524
140. Saha S, Liu-Yesucevitz L, Wolozin B (2014) Regulation of autophagy by LRRK2 in Caenorhabditis elegans. Neurodegener Dis 13(2–3):110–113. doi:10.1159/000355654
141. Son JH, Shim JH, Kim K-H, Ha J-Y, Han JY (2012) Neuronal autophagy and neurodegenerative diseases. Exp Mol Med 44(2):89–98. doi:10.3858/emm.2012.44.2.031
142. Plowey ED, Chu CT (2011) Synaptic dysfunction in genetic models of Parkinson’s disease: a role for autophagy? Neurobiol Dis 43(1):60–67. doi:10.1016/j.nbd.2010.10.011
143. Bravo-San Pedro JM, Niso-Santano M, Gómez-Sánchez R, Pizarro-Estrella E, Aiastui-Pujana A, Gorostidi A, Climent V, López de Maturana R, Sanchez-Pernaute R, López de Munain A, Fuentes JM, González-Polo RA (2012) The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway. Cell Mol Life Sci 70(1):121–136. doi:10.1007/s00018-012-1061-y
144. Manzoni C, Mamais A, Dihanich S, Abeti R, Soutar MP, Plun-Favreau H, Giunti P, Tooze SA, Bandopadhyay R, Lewis PA (2013) Inhibition of LRRK2 kinase activity stimulates macroautophagy. Biochim Biophys Acta 1833(12):2900–2910. doi:10.1016/j.bbamcr.2013.07.020
145. Schapansky J, Nardozzi JD, Felizia F, Lavoie MJ (2014) Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy. Hum Mol Genet. doi:10.1093/hmg/ddu138
146. Cherra SJ 3rd, Steer E, Gusdon AM, Kiselyov K, Chu CT (2013) Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol 182(2):474–484. doi:10.1016/j.ajpath.2012.10.027
147. Kahle PJ, Waak J, Gasser T (2009) DJ-1 and prevention of oxidative stress in Parkinson’s disease and other age-related disorders. Free Radic Biol Med 47(10):1354–1361. doi:10.1016/j.freeradbiomed.2009.08.003
148. Lu L, Sun X, Liu Y, Zhao H, Zhao S, Yang H (2012) DJ-1 upregulates tyrosine hydroxylase gene expression by activating its transcriptional factor Nurr1 via the ERK1/2 pathway. Int J Biochem Cell Biol 44(1):65–71. doi:10.1016/j.biocel.2011.09.007
149. Gao H, Yang W, Qi Z, Lu L, Duan C, Zhao C, Yang H (2012) DJ-1 protects dopaminergic neurons against rotenone-induced apoptosis by enhancing ERK-dependent mitophagy. J Mol Biol 423(2):232–248. doi:10.1016/j.jmb.2012.06.034
150. Krebiehl G, Ruckerbauer S, Burbulla LF, Kieper N, Maurer B, Waak J, Wolburg H, Gizatullina Z, Gellerich FN, Woitalla D, Riess O, Kahle PJ, Proikas-Cezanne T, Kruger R (2010) Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson’s disease-associated protein DJ-1. PLoS One 5(2). doi:10.1371/Journal.Pone.0009367
151. Ren HG, Fu K, Mu CC, Li B, Wang D, Wang GH (2010) DJ-1, a cancer and Parkinson’s disease associated protein, regulates autophagy through JNK pathway in cancer cells. Cancer Lett 297(1):101–108. doi:10.1016/j.canlet.2010.05.001
152. Cao J, Ying M, Xie N, Lin G, Dong R, Zhang J, Yan H, Yang X, He Q, Yang B (2014) The oxidation states of DJ-1 dictate the cell fate in response to oxidative stress triggered by 4-HPR: autophagy or apoptosis? Antioxid Redox Signal. doi:10.1089/ars.2013.5446
153. Irrcher I, Aleyasin H, Seifert EL, Hewitt SJ, Chhabra S, Phillips M, Lutz AK, Rousseaux MW, Bevilacqua L, Jahani-Asl A, Callaghan S, MacLaurin JG, Winklhofer KF, Rizzu P, Rippstein P, Kim RH, Chen CX, Fon EA, Slack RS, Harper ME, McBride HM, Mak TW, Park DS (2010) Loss of the Parkinson’s disease-linked gene DJ-1 perturbs mitochondrial dynamics. Hum Mol Genet 19(19):3734–3746. doi:10.1093/hmg/ddq288
154. Mccoy MK, Cookson MR (2011) DJ-1 regulation of mitochondrial function and autophagy through oxidative stress. Autophagy 7(5):531–532. doi:10.4161/auto.7.5.14684
155. Wu J, Lou H, Alerte TN, Stachowski EK, Chen J, Singleton AB, Hamilton RL, Perez RG (2012) Lewy-like aggregation of alpha-synuclein reduces protein phosphatase 2A activity in vitro and in vivo. Neuroscience 207:288–297. doi:10.1016/j.neuroscience.2012.01.028
156. Yang W, Wang X, Duan C, Lu L, Yang H (2013) Alpha-synuclein overexpression increases phospho-protein phosphatase 2A levels via formation of calmodulin/Src complex. Neurochem Int 63(3):180–194. doi:10.1016/j.neuint.2013.06.010
157. Lee KW, Chen W, Junn E, Im JY, Grosso H, Sonsalla PK, Feng X, Ray N, Fernandez JR, Chao Y, Masliah E, Voronkov M, Braithwaite SP, Stock JB, Mouradian MM (2011) Enhanced phosphatase activity attenuates alpha-synucleinopathy in a mouse model. J Neurosci 31(19):6963–6971. doi:10.1523/JNEUROSCI.6513-10.2011
158. Lou H, Montoya SE, Alerte TN, Wang J, Wu J, Peng X, Hong CS, Friedrich EE, Mader SA, Pedersen CJ, Marcus BS, McCormack AL, Di Monte DA, Daubner SC, Perez RG (2010) Serine 129 phosphorylation reduces the ability of alpha-synuclein to regulate tyrosine hydroxylase and protein phosphatase 2A in vitro and in vivo. J Biol Chem 285(23):17648–17661. doi:10.1074/jbc.M110.100867
159. Khandelwal PJ, Dumanis SB, Feng LR, Maguire-Zeiss K, Rebeck G, Lashuel HA, Moussa CE (2010) Parkinson-related parkin reduces alpha-synuclein phosphorylation in a gene transfer model. Mol Neurodegener 5:47. doi:10.1186/1750-1326-5-47
160. Qing H, Wong W, McGeer EG, McGeer PL (2009) Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications. Biochem Biophys Res Commun 387(1):149–152. doi:10.1016/j.bbrc.2009.06.142
161. Duplan E, Giaime E, Viotti J, Sevalle J, Corti O, Brice A, Ariga H, Qi L, Checler F, Alves da Costa C (2013) ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1. J Cell Sci 126(Pt 9):2124–2133. doi:10.1242/jcs.127340
162. Kim-Han JS, Antenor-Dorsey JA, O'Malley KL (2011) The parkinsonian mimetic, MPP+, specifically impairs mitochondrial transport in dopamine axons. J Neurosci 31(19):7212–7221. doi:10.1523/JNEUROSCI.0711-11.2011
163. Lim L, Jackson-Lewis V, Wong LC, Shui GH, Goh AX, Kesavapany S, Jenner AM, Fivaz M, Przedborski S, Wenk MR (2012) Lanosterol induces mitochondrial uncoupling and protects dopaminergic neurons from cell death in a model for Parkinson’s disease. Cell Death Differ 19(3):416–427. doi:10.1038/cdd.2011.105
164. Liu K, Shi N, Sun Y, Zhang T, Sun X (2013) Therapeutic effects of rapamycin on MPTP-induced Parkinsonism in mice. Neurochem Res 38(1):201–207. doi:10.1007/s11064-012-0909-8
165. Hung KC, Huang HJ, Lin MW, Lei YP, Lin AM (2014) Roles of autophagy in MPP+-induced neurotoxicity in vivo: the involvement of mitochondria and alpha-synuclein aggregation. PLoS One 9(3):e91074. doi:10.1371/journal.pone.0091074
166. Dagda RK, Das Banerjee T, Janda E (2013) How Parkinsonian toxins dysregulate the autophagy machinery. Int J Mol Sci 14(11):22163–22189. doi:10.3390/ijms141122163
167. Haque ME, Thomas KJ, D'Souza C, Callaghan S, Kitada T, Slack RS, Fraser P, Cookson MR, Tandon A, Park DS (2008) Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc Natl Acad Sci U S A 105(5):1716–1721. doi:10.1073/pnas.0705363105
168. Sallinen V, Kolehmainen J, Priyadarshini M, Toleikyte G, Chen YC, Panula P (2010) Dopaminergic cell damage and vulnerability to MPTP in Pink1 knockdown zebrafish. Neurobiol Dis 40(1):93–101. doi:10.1016/j.nbd.2010.06.001
169. Haque ME, Mount MP, Safarpour F, Abdel-Messih E, Callaghan S, Mazerolle C, Kitada T, Slack RS, Wallace V, Shen J, Anisman H, Park DS (2012) 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 287(27):23162–23170. doi:10.1074/jbc.M112.346437
170. Sul JW, Park MY, Shin J, Kim YR, Yoo SE, Kong YY, Kwon KS, Lee YH, Kim E (2013) Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration. Hum Mol Genet 22(8):1558–1573. doi:10.1093/hmg/ddt006
171. Aguiar AS Jr, Tristao FS, Amar M, Chevarin C, Lanfumey L, Mongeau R, Corti O, Prediger RD, Raisman-Vozari R (2013) Parkin-knockout mice did not display increased vulnerability to intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neurotox Res 24(2):280–287. doi:10.1007/s12640-013-9389-0
172. Dagda RK, Zhu J, Kulich SM, Chu CT (2008) Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress: implications for Parkinson’s disease. Autophagy 4(6):770–782
173. Zhu JH, Horbinski C, Guo F, Watkins S, Uchiyama Y, Chu CT (2007) Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death. Am J Pathol 170(1):75–86. doi:10.2353/ajpath.2007.060524
174. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB (2007) Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species. J Cell Sci 120(Pt 23):4155–4166. doi:10.1242/jcs.011163
175. Cagnol S, Chambard JC (2010) ERK and cell death: mechanisms of ERK-induced cell death—apoptosis, autophagy and senescence. FEBS J 277(1):2–21. doi:10.1111/j.1742-4658.2009.07366.x
176. Yu SW, Baek SH, Brennan RT, Bradley CJ, Park SK, Lee YS, Jun EJ, Lookingland KJ, Kim EK, Lee H, Goudreau JL, Kim SW (2008) Autophagic death of adult hippocampal neural stem cells following insulin withdrawal. Stem Cells 26(10):2602–2610. doi:10.1634/stemcells.2008-0153
177. Dias V, Junn E, Mouradian MM (2013) The role of oxidative stress in Parkinson’s disease. J Park Dis 3(4):461–491. doi:10.3233/JPD-130230
178. Li XY, Fang P, Mai JT, Choi ET, Wang H, Yang XF (2013) Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 6:19. doi:10.1186/1756-8722-6-19
179. Keane PC, Kurzawa M, Blain PG, Morris CM (2011) Mitochondrial dysfunction in Parkinson’s disease. Park Dis. doi:10.4061/2011/716871