α-突触核蛋白的代谢与聚集与蛋白酶体介导的非泛素依赖性降解相关。

alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome.

作者信息

Tofaris G K, Layfield R, Spillantini M G

机构信息

Cambridge Centre for Brain Repair and Neurology Department, University of Cambridge, Forvie Site, Robinson Way, CB2 2PY, Cambridge, UK.

出版信息

FEBS Lett. 2001 Nov 30;509(1):22-6. doi: 10.1016/s0014-5793(01)03115-5.

DOI:10.1016/s0014-5793(01)03115-5

PMID:11734199

Abstract

alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease based on mutations in familial cases of the disease and its presence in Lewy bodies. Here we show that over-expression of wild-type human alpha-synuclein is sufficient to induce inclusion formation in SH-SY5Y cells. In this cellular model, proteasome inhibition leads to an increase of alpha-synuclein accumulation in vivo without ubiquitylation. In accordance, we find that in vitro, unmodified alpha-synuclein can be directly degraded by the 20S proteasome. These findings suggest an ubiquitin-independent mechanism of proteasomal degradation for alpha-synuclein and other natively unfolded proteins.

摘要

基于帕金森病家族性病例中的突变以及其在路易小体中的存在，α-突触核蛋白已被认为与帕金森病的发病机制有关。在此我们表明，野生型人α-突触核蛋白的过表达足以在SH-SY5Y细胞中诱导包涵体形成。在这个细胞模型中，蛋白酶体抑制导致体内α-突触核蛋白积累增加而无泛素化。相应地，我们发现在体外，未修饰的α-突触核蛋白可被20S蛋白酶体直接降解。这些发现提示了一种α-突触核蛋白及其他天然未折叠蛋白的蛋白酶体降解的非泛素依赖性机制。