Deubiquitinase Usp8 regulates alpha-synuclein clearance and modifies its toxicity in Lewy body disease

作者：Alexopoulou Zoi; Lang Johannes; Perrett Rebecca M; Elschami Myriam; Hurry Madeleine E D; Kim Hyoung Tae; Mazaraki Dimitra; Szabo Aron; Kessler Benedikt M; Goldberg Alfred Lewis; Ansorge Olaf; Fulga Tudor A; Tofaris George K^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(32): E4688-E4697.

DOI：10.1073/pnas.1523597113

• ubiquitin
• Parkinson's disease
• endosome
• ubiquitin ligase
• neurodegeneration

In Parkinson's disease, misfolded alpha-synuclein accumulates, often in a ubiquitinated form, in neuronal inclusions termed Lewy bodies. An important outstanding question is whether ubiquitination in Lewy bodies is directly relevant to alpha-synuclein trafficking or turnover and Parkinson's pathogenesis. By comparative analysis in human postmortem brains, we found that ubiquitin immunoreactivity in Lewy bodies is largely due to K63-linked ubiquitin chains and markedly reduced in the substantia nigra compared with the neocortex. The ubiquitin staining in cells with Lewy bodies inversely correlated with the content and pathological localization of the deubiquitinase Usp8. Usp8 interacted and partly colocalized with alpha-synuclein in endosomal membranes and, both in cells and after purification, it deubiquitinated K63-linked chains on alpha-synuclein. Knockdown of Usp8 in the Drosophila eye reduced alpha-synuclein levels and alpha-synuclein-induced eye toxicity. Accordingly, in human cells, Usp8 knockdown increased the lysosomal degradation of alpha-synuclein. In the dopaminergic neurons of the Drosophila model, unlike knockdown of other deubiquitinases, Usp8 protected from alpha-synuclein-induced locomotor deficits and cell loss. These findings strongly suggest that removal of K63-linked ubiquitin chains on alpha-synuclein by Usp8 is a critical mechanism that reduces its lysosomal degradation in dopaminergic neurons and may contribute to alpha-synuclein accumulation in Lewy body disease.

• 出版日期2016-8-9