The deposition of α-synuclein (α-Syn) fibrils in neuronal cells has been implicated as a causative factor in Parkinson's disease (PD) and dementia with Lewy Bodies (DLB). α-Syn can be degraded by autophagy, proteasome, and chaperone-mediated autophagy, and previous studies have suggested the potency of certain cathepsins, lysosomal proteases, for α-Syn degradation. However, no studies have comprehensively evaluated all cathepsins. Here, we evaluated the efficacy of all 15 cathepsins using a cell model of α-Syn fibril propagation and found that overexpression of cathepsin L (CTSL) was the most effective in preventing the accumulation of α-Syn aggregates. CTSL-mediated degradation of α-Syn aggregates was dependent on the autophagy machinery, and CTSL itself promoted autophagy flux. Interestingly, CTSL was effective in autophagic degradation of wild-type (WT) α-Syn, but not in the case of A53T and E46K missense mutations, which are causative for familial PD. These results suggest that CTSL is a potential therapeutic strategy for sporadic PD pathology in WT α-Syn.

中文翻译：

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组织蛋白酶 L 防止细胞内 α-突触核蛋白原纤维的积累

神经元细胞中 α-突触核蛋白 (α-Syn) 原纤维的沉积被认为是帕金森病 (PD) 和路易体痴呆 (DLB) 的致病因素。 α-Syn 可以被自噬、蛋白酶体和伴侣介导的自噬降解，之前的研究表明某些组织蛋白酶、溶酶体蛋白酶对 α-Syn 降解具有效力。然而，还没有研究全面评估所有组织蛋白酶。在这里，我们使用 α-Syn 原纤维增殖的细胞模型评估了所有 15 种组织蛋白酶的功效，发现组织蛋白酶 L (CTSL) 的过表达在防止 α-Syn 聚集体的积累方面最有效。 CTSL 介导的 α-Syn 聚集体降解依赖于自噬机制，并且 CTSL 本身促进自噬通量。有趣的是，CTSL 对野生型 (WT) α-Syn 的自噬降解有效，但对导致家族性 PD 的 A53T 和 E46K 错义突变无效。这些结果表明 CTSL 是 WT α-Syn 散发性 PD 病理的潜在治疗策略。