Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK.
UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK.
Autophagy. 2023 Apr;19(4):1348-1350. doi: 10.1080/15548627.2022.2116832. Epub 2022 Aug 28.
The ability to maintain a functional proteome by clearing damaged or misfolded proteins is critical for cell survival, and aggregate-prone proteins accumulate in many neurodegenerative diseases, such as Huntington, Alzheimer, and Parkinson diseases. The removal of such proteins is mainly mediated by the ubiquitin-proteasome system and autophagy, and the activity of these systems declines in disease or with age. We recently found that targeting VCP/p97 with compounds like SMER28 enhances macroautophagy/autophagy flux mediated by the increased activity of the PtdIns3K complex I. Additionally, we found that SMER28 binding to VCP stimulates aggregate-prone protein clearance via the ubiquitin-proteasome system. This concurrent action of SMER28 on both degradation pathways resulted in the selective decrease in disease-causing proteins but not their wild-type counterparts. These results reveal a promising mode of VCP activation to counteract the toxicity caused by aggregate-prone proteins.
通过清除受损或错误折叠的蛋白质来维持功能蛋白组的能力对细胞存活至关重要，而且在许多神经退行性疾病（如亨廷顿病、阿尔茨海默病和帕金森病）中，易于聚集的蛋白质会积累。这些蛋白质的清除主要由泛素-蛋白酶体系统和自噬介导，并且这些系统的活性在疾病或衰老时会下降。我们最近发现，用 SMER28 等化合物靶向 VCP/p97 可以增强由 PtdIns3K 复合物 I 活性增加介导的巨自噬/自噬流。此外，我们发现 SMER28 与 VCP 的结合通过泛素-蛋白酶体系统刺激易于聚集的蛋白质清除。SMER28 对这两种降解途径的同时作用导致疾病相关蛋白选择性减少，而其野生型蛋白则不受影响。这些结果揭示了一种有前途的 VCP 激活模式，以对抗易于聚集的蛋白质引起的毒性。
