Inhibition of proteasomal activity causes inclusion formation in neuronal and non-neuronal cells overexpressing Parkin
Inhibition of proteasomal activity causes inclusion formation in neuronal and non-neuronal cells overexpressing Parkin
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DOI：
10.1091/mbc.e03-02-0078
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发表时间：
2003-11-01
影响因子：
3.3
通讯作者：
Robinson, PA
中科院分区：
文献类型：
--
作者：
Ardley, HC;Scott, GB;Robinson, PA
蛋白质内含物与神经退行性疾病（包括帕金森病和阿尔茨海默病以及多聚谷氨酰胺疾病）之间的关联已被广泛记录。虽然泛素与许多这些聚集的蛋白质结合，但26 S蛋白酶体不能有效地降解它们。泛蛋白连接酶帕金基因突变与常染色体隐性遗传青少年帕金森综合征相关虽然在常染色体隐性遗传的青少年帕金森综合征患者的脑中未检测到Parkin阳性包涵体，但在散发性疾病的路易体中发现了Parkin。这表明，帕金连接酶活性的损失，通过突变，或隔离路易体，是一个促成因素，散发性疾病发作。我们现在证明，蛋白酶体活性下降导致形成大的，非细胞毒性的包涵体内的神经元和非神经元细胞的细胞质过度表达帕金。这不是一种普遍现象，因为当HHARI（Parkin的结构同源物）过表达时，不存在类似的内含物。包涵体与泛素和蛋白酶体共定位。此外，帕金包涵体与γ-微管蛋白、乙酰化α-微管蛋白共定位，并引起波形蛋白的重新分布，表明侵袭体样性质。我们的数据表明，较低的蛋白酶体活性，以前在帕金森氏病患者的脑组织中观察到，导致帕金积累和连接酶活性的伴随减少，从而促进路易体形成。
Association between protein inclusions and neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, and polyglutamine disorders, has been widely documented. Although ubiquitin is conjugated to many of these aggregated proteins, the 26S proteasome does not efficiently degrade them. Mutations in the ubiquitin-protein ligase Parkin are associated with autosomal recessive juvenile Parkinsonism. Although Parkin-positive inclusions are not detected in brains of autosomal recessive juvenile Parkinsonism patients, Parkin is found in Lewy bodies in sporadic disease. This suggests that loss of Parkin ligase activity via mutation, or sequestration to Lewy bodies, is a contributory factor to sporadic disease onset. We now demonstrate that decreased proteasomal activity causes formation of large, noncytotoxic inclusions within the cytoplasm of both neuronal and nonneuronal cells overexpressing Parkin. This is not a general phenomenon as there is an absence of similar inclusions when HHARI, a structural homolog of Parkin, is overexpressed. The inclusions colocalize with ubiquitin and with proteasomes. Furthermore, Parkin inclusions colocalize with gamma-tubulin, acetylated alpha-tubulin, and cause redistribution of vimentin, suggesting aggresome-like properties. Our data imply that lower proteasomal activity, previously observed in brain tissue of Parkinson's disease patients, leads to Parkin accumulation and a concomitant reduction in ligase activity, thereby promoting Lewy body formation.