Institute for Biomedicine, Sahlgrenska Academy, Centre for Ageing and Health-AgeCap, University of Gothenburg, Sweden.
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Sweden.
FEBS J. 2020 Dec;287(23):5068-5079. doi: 10.1111/febs.15345. Epub 2020 May 10.
Central to proteopathies and leading to most age-related neurodegenerative disorders is a failure in protein quality control (PQC). To harness the toxicity of misfolded and damaged disease proteins, such proteins are either refolded, degraded by temporal PQC, or sequestered by spatial PQC into specific, organelle-associated, compartments within the cell. Here, we discuss the impact of vesicle trafficking pathways in general, and syntaxin 5 in particular, as key players in spatial PQC directing misfolded proteins to the surface of vacuole and mitochondria, which facilitates their clearance and detoxification. Since boosting vesicle trafficking genetically can positively impact on spatial PQC and make cells less sensitive to misfolded disease proteins, we speculate that regulators of such trafficking might serve as therapeutic targets for age-related neurological disorders.
蛋白质质量控制（PQC）的失败是蛋白病变和导致大多数与年龄相关的神经退行性疾病的核心。为了利用错误折叠和受损的疾病蛋白的毒性，这些蛋白要么被重新折叠，要么通过暂时的 PQC 降解，要么通过空间 PQC 被隔离到细胞内特定的、与细胞器相关的隔室中。在这里，我们讨论了囊泡运输途径的影响，特别是突触融合蛋白 5（syntaxin 5）作为空间 PQC 的关键因子，将错误折叠的蛋白引导到液泡和线粒体的表面，从而促进其清除和解毒。由于遗传上增强囊泡运输可以积极影响空间 PQC 并使细胞对错误折叠的疾病蛋白的敏感性降低，我们推测这种运输的调节剂可能成为与年龄相关的神经障碍的治疗靶点。
