Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain

Journal of Neuroscience

Volumn 32, Issue 22, 2012, Pages 7585-7593

  Friedman, Lauren G ^a   Lachenmayer, M Lenard ^a,c   Wang, Jing ^a   He, Liqiang ^a   Poulose, Shibu M ^a,d   Komatsu, Masaaki ^b   Holstein, Gay R ^a   Yue, Zhenyu ^a  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^b TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE   (Japan)

^c UNIVERSITY OF BONN   (Germany)

^d TUFTS UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SYNUCLEIN; LEUCINE RICH REPEAT KINASE 2; PROTEIN P62; TYROSINE 3 MONOOXYGENASE; UBIQUITIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; ATG7 GENE; AUTOPHAGY; BEHAVIOR; CELL DEATH; CONTROLLED STUDY; DOPAMINERGIC NERVE CELL; DYSTROPHY; ELECTRON MICROSCOPY; EMBRYO; FEMALE; GENE; GENE DELETION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IMMUNOHISTOCHEMISTRY; KNOCKOUT MOUSE; LOCOMOTION; MALE; MESENCEPHALON; MOUSE; NERVE CELL DEGENERATION; NERVE FIBER DEGENERATION; NONHUMAN; PARKINSON DISEASE; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; STEREOLOGY; WESTERN BLOTTING;

ALPHA-SYNUCLEIN; ANIMALS; AUTOPHAGY; BRAIN; CELLS, CULTURED; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DENDRITES; DISEASE MODELS, ANIMAL; DOPAMINE; DOPAMINERGIC NEURONS; EMBRYO, MAMMALIAN; EPHRIN-B1; FIBROBLASTS; GENE EXPRESSION REGULATION; INCLUSION BODIES; INTERMEDIATE FILAMENT PROTEINS; MICE; MICE, TRANSGENIC; MICROTUBULE-ASSOCIATED PROTEINS; MOTOR ACTIVITY; MOVEMENT DISORDERS; NERVE DEGENERATION; NERVE TISSUE PROTEINS; PRESYNAPTIC TERMINALS; TYROSINE 3-MONOOXYGENASE; UBIQUITIN;

EID: 84861595545     PISSN: 02706474     EISSN: 15292401     Source Type: Journal    
DOI: 10.1523/JNEUROSCI.5809-11.2012     Document Type: Article

References (30)

1. Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, An-sorge O, Wade-Martins R (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet 18:4022-4034.
2. Bywood PT, Johnson SM (2000) Dendrite loss is a characteristic early indicator of toxin-induced neurodegeneration in rat midbrain slices. Exp Neurol 161:306-316.
3. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292-1295.
4. Dauer W, Przedborski S (2003) Parkinson's disease: mechanisms and models. Neuron 39:889-909.
5. Duda JE, Giasson BI, Mabon ME, Lee VM, Trojanowski JQ (2002) Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases. Ann Neurol 52:205-210.
6. Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, Rockenstein E, Masliah E, Hyman BT, McLean PJ, Unni VK (2011) Distinct roles in vivo for the ubiquitin-proteasome system and the autophagy-lysosomal pathway in the degradation of a-synuclein. J Neurosci 31:14508-14520.
7. Fleming SM, Salcedo J, Fernagut PO, Rockenstein E, Masliah E, Levine MS, Chesselet MF (2004) Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. J Neurosci 24:9434-9440.
8. 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 441:885-889.
9. Jiao Y, Sun Z, Lee T, Fusco FR, Kimble TD, Meade CA, Cuthbertson S, Reiner A (1999) A simple and sensitive antigen retrieval method for free-floating and slide-mounted tissue sections. J Neurosci Methods 93:149-162.
10. Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, Ohsumi M, Takao T, Noda T, Ohsumi Y (2000) The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. J Cell Biol 151:263-276.
11. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880-884.
12. Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr, Iwata J, Kominami E, Chait BT, Tanaka K, Yue Z (2007a) Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci USA 104:14489-14494.
13. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, et al. (2007b) Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131:1149-1163.
14. Li X, Patel JC, Wang J, Avshalumov MV, Nicholson C, Buxbaum JD, Elder GA, Rice ME, Yue Z (2010) Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson's disease mutation G2019S. J Neurosci 30: 1788-1797.
15. Lichtenberg M, Mansilla A, Zecchini VR, Fleming A, Rubinsztein DC (2011) The Parkinson's disease protein LRRK2 impairs proteasome substrate clearance without affecting proteasome catalytic activity. Cell Death Dis 2:e196.
16. Lin X, Parisiadou L, Gu XL, Wang L, Shim H, Sun L, Xie C, Long CX, Yang WJ, Ding J, Chen ZZ, Gallant PE, Tao-Cheng JH, Rudow G, Troncoso JC, Liu Z, Li Z, Cai H (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 64:807-827.
17. Lindeberg J, Usoskin D, Bengtsson H, Gustafsson A, Kylberg A, Soderstrom S, Ebendal T (2004) Transgenic expression of Cre recombinase from the tyrosine hydroxylase locus. Genesis 40:67-73.
18. Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, Tokuhisa T, Ohsumi Y, Yoshimori T (2001) Dissection of autophago-some formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 152:657-668.
19. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069-1075.
20. Nishiyama J, Miura E, Mizushima N, Watanabe M, Yuzaki M (2007) Aberrant membranes and double-membrane structures accumulate in the axons of Atg5-null Purkinje cells before neuronal death. Autophagy 3:591-596.
21. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45.
22. Plowey ED, Cherra SJ 3rd, Liu YJ, Chu CT (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105:1048-1056.
23. Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, et al. (2011) Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One 6:e18568.
24. Rideout HJ, Lang-Rollin I, Stefanis L (2004) Involvement of macroau-tophagy in the dissolution of neuronal inclusions. Int J Biochem Cell Biol 36:2551-2562.
25. 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 29:13578-13588.
26. Wang QJ, Ding Y, Kohtz DS, Kohtz S, Mizushima N, Cristea IM, Rout MP, Chait BT, Zhong Y, Heintz N, Yue Z (2006) Induction of autophagy in axonal dystrophy and degeneration. J Neurosci 26:8057-8068.
27. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278:25009-25013.
28. 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) A-synuclein impairs macroau-tophagy: implications for Parkinson's disease. J Cell Biol 190:1023-1037.
29. Yu WH, Dorado B, Figueroa HY, Wang L, Planel E, Cookson MR, Clark LN, Duff KE (2009) Metabolic activity determines efficacy of macroau-tophagic clearance of pathological oligomeric alpha-synuclein. Am J Pathol 175:736-747.
30. Zhu X, Siedlak SL, Smith MA, Perry G, Chen SG (2006) LRRK2 protein is a component of Lewy bodies. Ann Neurol 60:617-618; author reply 618-619.