Molecular analyses of cell death and vacuole formation that are induced by abnormal protein accumulation

在神经退行性疾病中，蛋白质聚集体和空泡几乎普遍存在于退化的神经元中，表明在神经元细胞死亡中存在类似的分子过程。事实上，包括亨廷顿病在内的9种遗传性神经退行性疾病已被证明是由编码多聚谷氨酰胺的CAG重复序列的扩增引起的。我们已经确定VCP，AAA ATP酶的成员，作为神经退行性变的关键分子。即，1）VCP与多聚谷氨酰胺聚集体和其他蛋白质聚集体（如帕金森病中的Lewy小体）共定位; 2）发现VCP的ATP酶活性的严重缺陷严重影响ER质量控制，导致异常ER扩增和细胞死亡，这是在许多神经退行性疾病中经常观察到的表型; 3）VCP具有解折叠错误折叠蛋白的潜力;（4）VCP中的几个氨基酸被修饰：（5）修饰后的VCP具有不同的ATP酶活性。这些证据表明，异常蛋白质的过度积累可能会在几种神经退行性疾病中通过其（错误）修饰破坏VCP的ATP酶，最终导致神经退行性变。因此，提出了VCP功能的适当调节，以导致在广泛的神经退行性疾病中有效的新治疗。

In neurodegenerative disorders, protein aggregates and vacuoles are almost universally found in degenerating neurons, suggesting the existence of similar molecular processes in, neuronal cell death. Indeed, 9 inherited neurodegenerative diseases, including Huntington disease have been shown to be caused by the expansion of CAG repeats encoding polyglutamines. We have identified VCP, a member of the AAA ATPase, as a key molecule in neurodegeneration. Namely, 1) VCP co-localizes with polyglutamine aggregates and other protein aggregates such as Lewy bodies in Parkinson disease; 2) Profound deficits in VCP's ATPase activity are found to severely affect ER quality control, leading to abnormal ER expansion and cell death, phenotypes frequently observed in many neurodegenerative diseases; 3) VCP has a potential to unfold misfolded proteins; 4) several amino acid in VCP are modified; 5) Modified VCP shows different ATPase activities. These lines of evidence raise the possibility that excessive accumulation of abnormal proteins may inactivate, VCP's ATPase via its (mis)modification in several neurodegenerative disorders, eventually leading to the neurodegenerations. A proper regulation of VCP function is thus proposed to lead to novel treatments that are effective in a broad spectrum of neurodegenerative diseases.