Molecular analysis on nqurodegeneration

神经细胞死亡、异常蛋白聚集和细胞质空泡化是许多神经退行性疾病（如聚谷氨酰胺病、朊病毒病、阿尔茨海默病和路易体病）中观察到的主要病理，提示神经退行性疾病的共同机制。本研究在体外和体内鉴定出AAA+ ATPase蛋白家族成员VCP/p97为多q相互作用蛋白，并报道了其特性。内源性VCP在表达前polyQ的培养细胞中与扩增的polyQ（前polyQ）聚集体共定位，在亨廷顿病患者大脑中与核包涵体共定位，在患者样本中与路易小体共定位。此外，第二ATP结合域突变的VCP突变体的表达产生细胞质空泡，随后导致细胞死亡。expolyQ表达或蛋白酶体抑制剂处理也能诱导出非常相似的空泡。这些结果表明，VCP不仅是异常折叠蛋白的识别因子，而且是几种神经退行性表型的病理效应因子。因此，VCP可能是治疗神经退行性疾病的理想分子靶点。

Neuronal cell death, abnormal protein aggregates, and cytoplasmic vacuolization are major pathologies observed in many neurodegenerative disorders such as the polyglutamine (polyQ) diseases, prion disease, Alzheimer disease, and the Lewy body diseases, suggesting common mechanisms underlying neurodegeneration. Here, we have identified VCP/p97, a member of the AAA+ family of ATPase proteins, as a polyQ-interacting protein in vitro and in vivo, and report on its characterization. Endogenous VCP co-localized with expanded polyQ (ex-polyQ) aggregates in cultured cells expressing ex-polyQ, with nuclear inclusions in Huntington disease patient brains, and with Lewy bodies in patient samples. Moreover, the expression of VCP mutants with mutations in the 2nd ATP binding domain created cytoplasmic vacuoles, followed by cell death. Very similar vacuoles were also induced by expolyQ expression or proteasome inhibitor treatment. These results suggest that VCP functions not only as a recognition factor for abnormally folded proteins but also as a pathological effector for several neurodegenerative phenotypes. VCP may thus be an ideal molecular target for the treatment of neurodegenerative disorders.