Staerz Sophia D, Anamoah Charles, Tepe Jetze J
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
iScience. 2024 Jun 4;27(7):110166. doi: 10.1016/j.isci.2024.110166. eCollection 2024 Jul 19.
Synucleinopathies are a class of neurodegenerative diseases defined by the presence of α-synuclein inclusions. The location and composition of these α-synuclein inclusions directly correlate to the disease pattern. The inclusions in Multiple System Atrophy are located predominantly in oligodendrocytes and are rich in a second protein, p25α. P25α plays a key role in neuronal myelination by oligodendrocytes. In healthy oligodendrocytes, there is little to no α-synuclein present. If aberrant α-synuclein is present, p25α leaves the myelin sheaths and quickly co-aggregates with α-synuclein, resulting in the disruption of the cellular process and ultimately cell death. Herein, we report that p25α is susceptible for 20S proteasome-mediated degradation and that p25α induces α-synuclein aggregation, resulting in proteasome impairment and cell death. In addition, we identified small molecules 20S proteasome enhancers that prevent p25α induced α-synuclein fibrilization, restore proteasome impairment, and enhance cell viability.
突触核蛋白病是一类由α-突触核蛋白包涵体的存在所定义的神经退行性疾病。这些α-突触核蛋白包涵体的位置和组成与疾病模式直接相关。多系统萎缩中的包涵体主要位于少突胶质细胞中，并且富含另一种蛋白质p25α。P25α在少突胶质细胞对神经元的髓鞘形成中起关键作用。在健康的少突胶质细胞中，几乎没有α-突触核蛋白存在。如果存在异常的α-突触核蛋白，p25α会离开髓鞘并迅速与α-突触核蛋白共同聚集，导致细胞过程中断并最终导致细胞死亡。在此，我们报告p25α易受20S蛋白酶体介导的降解作用，并且p25α诱导α-突触核蛋白聚集，导致蛋白酶体功能受损和细胞死亡。此外，我们鉴定出小分子20S蛋白酶体增强剂，其可防止p25α诱导的α-突触核蛋白纤维化，恢复蛋白酶体功能受损，并增强细胞活力。
