UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease
UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease
复制标题
DOI：
10.1111/j.1471-4159.2004.02485.x
复制
发表时间：
2004-07-01
影响因子：
4.7
通讯作者：
Robinson, PA
中科院分区：
文献类型：
--
作者：
Ardley, HC;Scott, GB;Robinson, PA
攻击体与许多神经退行性疾病相关，包括帕金森病和多聚谷氨酰胺疾病如亨廷顿病。这些内含物通常含有泛素化蛋白。这些蛋白质被泛素化的阶段仍不清楚。泛蛋白/蛋白酶体系统（UPS）的故障可能与它们的形成有关。相反，它可能反映细胞试图移除它们的不成功尝试。以前，我们证明了过度表达的帕金，泛素蛋白连接酶与常染色体隐性青少年帕金森综合征，产生侵略样夹杂物UPS受损的细胞。去泛素化酶UCH-L1的突变会导致一种罕见的帕金森病。我们现在证明，UCH-L1的过度表达也形成响应于蛋白酶体抑制的带状侵袭体。疾病相关的突变，影响酶活性，显着增加了夹杂物的数量。UCH-L1侵袭体与泛素化蛋白、HSP 70、γ-微管蛋白共定位，并且在较小程度上与20 S蛋白酶体和伴侣BiP共定位。与Parkin包涵体类似，我们发现UCH-L1攻击体被微管蛋白而不是波形蛋白笼状结构包围。此外，UCH-L1与帕金和α-突触核蛋白在一些但不是所有包涵体中聚集，表明这些包涵体的异质性。这项研究提供了额外的证据表明，易于聚集的蛋白质可能会招募UPS组件，试图从失败的蛋白酶体中清除蛋白质。此外，UCH-L1积累可能在帕金森病的包涵体形成中发挥病理作用。
Aggresomes are associated with many neurodegenerative disorders, including Parkinson's disease, and polyglutamine disorders such as Huntington's disease. These inclusions commonly contain ubiquitylated proteins. The stage at which these proteins are ubiquitylated remains unclear. A malfunction of the ubiquitin/proteasome system (UPS) may be associated with their formation. Conversely, it may reflect an unsuccessful attempt by the cell to remove them. Previously, we demonstrated that overexpression of Parkin, a ubiquitin-protein ligase associated with autosomal recessive juvenile Parkinsonism, generates aggresome-like inclusions in UPS compromised cells. Mutations in the de-ubiquitylating enzyme, UCH-L1, cause a rare form of Parkinsonism. We now demonstrate that overexpression of UCH-L1 also forms ribbon-like aggresomes in response to proteasomal inhibition. Disease-associated mutations, which affect enzymatic activities, significantly increased the number of inclusions. UCH-L1 aggresomes co-localized with ubiquitylated proteins, HSP70, gamma-tubulin and, to a lesser extent, the 20S proteasome and the chaperone BiP. Similar to Parkin inclusions, we found UCH-L1 aggresomes to be surrounded by a tubulin rather than a vimentin cage-like structure. Furthermore, UCH-L1 aggregates with Parkin and alpha-synuclein in some, but not all inclusions, suggesting the heterogeneous nature of these inclusion bodies. This study provides additional evidence that aggregation-prone proteins are likely to recruit UPS components in an attempt to clear proteins from failing proteasomes. Furthermore, UCH-L1 accumulation is likely to play a pathological role in inclusion formation in Parkinson's disease.