Parkinson's disease is a progressive neurodegenerative disorder characterised by the accumulation of misfolded α-synuclein in selected brain regions, including the substantia nigra pars compacta (SNpc), where marked loss of dopaminergic neurons is also observed. Yet, the relationship between misfolded α-synuclein and neurotoxicity currently remains unclear. As the principal route for degradation of misfolded proteins in mammalian cells, the ubiquitin-proteasome system (UPS) is critical for maintenance of cellular proteostasis. Misfolded α-synuclein impairs UPS function and contributes to neuronal death in vitro. Here, we examine its effects in vivo using adeno-associated viruses to co-express A53T α-synuclein and the ubiquitinated reporter protein UbG76V-GFP in rat SNpc. We found that α-synuclein over-expression leads to early-onset catalytic impairment of the 26S proteasome with associated UPS dysfunction, preceding the onset of behavioural deficits and dopaminergic neurodegeneration. UPS failure in dopaminergic neurons was also associated with selective accumulation of α-synuclein phosphorylated at the serine 129 residue, which has previously been linked to increased neurotoxicity. Our study highlights a role for α-synuclein in disturbing proteostasis which may contribute to neurodegeneration in vivo.

中文翻译：

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α-突触核蛋白引起的多巴胺能神经元中泛素-蛋白酶体系统的早期发作损伤。

帕金森氏病是一种进行性神经退行性疾病，其特征是错误折叠的α-突触核蛋白在选定的大脑区域（包括黑质致密部黑斑病（SNpc））中积聚，在那里还观察到多巴胺能神经元的明显丧失。然而，错误折叠的α-突触核蛋白与神经毒性之间的关系目前仍不清楚。作为降解哺乳动物细胞中错误折叠的蛋白质的主要途径，泛素-蛋白酶体系统（UPS）对于维持细胞蛋白稳定至关重要。错误折叠的α-突触核蛋白会损害UPS功能，并在体外导致神经元死亡。在这里，我们检查了其在体内的作用，使用腺相关病毒在大鼠SNpc中共表达A53Tα-突触核蛋白和泛素化的报道蛋白UbG76V-GFP。我们发现，α-突触核蛋白的过度表达会导致26S蛋白酶体的早期发作催化损伤，并伴有UPS功能障碍，先于行为缺陷和多巴胺能神经变性发作。多巴胺能神经元中的UPS故障还与在丝氨酸129残基处磷酸化的α-突触核蛋白的选择性积累有关，这以前与神经毒性增加有关。我们的研究突出了α-突触核蛋白在扰动蛋白变性中的作用，这可能会导致体内神经变性。以前与神经毒性增加有关。我们的研究突出了α-突触核蛋白在扰动蛋白变性中的作用，这可能会导致体内神经变性。以前与神经毒性增加有关。我们的研究突出了α-突触核蛋白在扰动蛋白变性中的作用，这可能会导致体内神经变性。