Flechsig Institute for Brain Research, University of Leipzig, 04103 Leipzig, Germany.
Department for Experimental Therapy, University Clinics Erlangen and Preclinical Experimental Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Int J Mol Sci. 2021 May 21;22(11):5450. doi: 10.3390/ijms22115450.
In Parkinson's disease, aggregates of α-synuclein within Lewy bodies and Lewy neurites represent neuropathological hallmarks. However, the cellular and molecular mechanisms triggering oligomeric and fibrillary α-synuclein aggregation are not fully understood. Recent evidence indicates that oxidative stress induced by metal ions and post-translational modifications such as phosphorylation, ubiquitination, nitration, glycation, and SUMOylation affect α-synuclein conformation along with its aggregation propensity and neurotoxic profiles. In addition, proteolytic cleavage of α-synuclein by specific proteases results in the formation of a broad spectrum of fragments with consecutively altered and not fully understood physiological and/or pathological properties. In the present review, we summarize the current knowledge on proteolytical α-synuclein cleavage by neurosin, calpain-1, cathepsin D, and matrix metalloproteinase-3 in health and disease. We also shed light on the contribution of the same enzymes to proteolytical processing of pathogenic proteins in Alzheimer's disease and report potential cross-disease mechanisms of pathogenic protein aggregation.
在帕金森病中，α-突触核蛋白在路易小体和路易神经突内的聚集代表了神经病理学的特征。然而，触发寡聚体和纤维状α-突触核蛋白聚集的细胞和分子机制尚不完全清楚。最近的证据表明，金属离子诱导的氧化应激和翻译后修饰，如磷酸化、泛素化、硝化、糖化和 SUMO 化，影响α-突触核蛋白的构象及其聚集倾向和神经毒性特征。此外，α-突触核蛋白被特定蛋白酶的蛋白水解切割会导致形成一系列片段，这些片段具有连续改变的、不完全了解的生理和/或病理特性。在本综述中，我们总结了神经丝氨酸、钙蛋白酶-1、组织蛋白酶 D 和基质金属蛋白酶-3 在健康和疾病状态下对α-突触核蛋白的蛋白水解切割的最新认识。我们还阐明了相同酶对阿尔茨海默病中致病性蛋白蛋白水解加工的贡献，并报告了致病性蛋白聚集的潜在跨疾病机制。
