Dopamine-modified α-synuclein blocks chaperone-mediated autophagy

被引:520
|
作者
Martinez-Vicente, Marta [1 ,2 ]
Talloczy, Zsolt [3 ,4 ,5 ,6 ]
Kaushik, Susmita [1 ,2 ]
Massey, Ashish C. [1 ,2 ]
Mazzulli, Joseph [7 ,8 ,9 ]
Mosharov, Eugene V. [3 ,4 ,5 ,6 ]
Hodara, Roberto [7 ,8 ,9 ]
Fredenburg, Ross [10 ]
Wu, Du-Chu [5 ,6 ,11 ]
Follenzi, Antonia [2 ]
Dauer, William [5 ,6 ]
Przedborski, Serge [5 ,6 ,11 ]
Lschiropoulos, Harry [7 ,8 ,9 ]
Lansbury, Peter T. [10 ]
Sulzer, David [3 ,4 ,5 ,6 ]
Cuervo, Ana Maria [1 ,2 ]
机构
[1] Yeshiva Univ Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10461 USA
[2] Yeshiva Univ Albert Einstein Coll Med, Marion Bessin Liver Res Ctr, Bronx, NY 10461 USA
[3] Columbia Univ, Dept Psychiat, New York, NY USA
[4] Columbia Univ, Dept Pharm, New York, NY USA
[5] Columbia Univ, Dept Neurol, New York, NY USA
[6] Columbia Univ, New York State Psychiat Inst, Dept Neurosci, New York, NY USA
[7] Univ Penn, Philadelphia, PA 19104 USA
[8] Stokes Res Inst, Philadelphia, PA USA
[9] Childrens Hosp Philadelphia, Dept Pediat & Pharmacol, Philadelphia, PA 19104 USA
[10] Harvard Univ, Sch Med, Dept Neurol, Brigham & Womens Hosp,Ctr Neurol Dis, Cambridge, MA 02138 USA
[11] Columbia Univ, Dept Pathol & Cell Biol, Dept Neurosci, New York State Psychiat Inst, New York, NY USA
来源
JOURNAL OF CLINICAL INVESTIGATION | 2008年 / 118卷 / 02期
关键词
D O I
10.1172/JCI32806
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Altered degradation of alpha-synuclein (alpha-syn) has been implicated in the pathogenesis of Parkinson disease (PD). We have shown that alpha-syn can be degraded via chaperone-mediated autophagy (CMA), a selective lysosomal mechanism for degradation of cytosolic proteins. Pathogenic mutants of alpha-syn block lysosomal translocation, impairing their own degradation along with that of other CMA substrates. While pathogenic alpha-syn mutations are rare, alpha-syn undergoes posttranslational modifications, which may underlie its accumulation in cytosolic aggregates in most forms of PD. Using mouse ventral medial neuron cultures, SH-SY5Y cells in culture, and isolated mouse lysosomes, we have found that most of these posttranslational modifications of alpha-syn impair degradation of this protein by CMA but do not affect degradation of other substrates. Dopamine-modified alpha-syn, however, is not only poorly degraded by CMA but also blocks degradation of other substrates by this pathway. As blockage of CMA increases cellular vulnerability to stressors, we propose that dopamine-induced autophagic inhibition could explain the selective degeneration of PD dopaminergic neurons.
引用
收藏
页码:777 / 788
页数:12
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