自噬介导α-突触核蛋白清除在帕金森病发生发展中的作用

Roles of autophagy-mediated alpha-synuclein clearance in the development of Parkinson disease

帕金森病(Parkinson disease,PD)是一种常见的慢性神经退行性疾病,严重影响患者的生活质量,已成为社会面临的重要人口健康问题。PD的典型神经病理学特征是α-突触核蛋白(α-synuclein,α-Syn)在黑质-纹状体区的异常聚集,造成多巴胺能神经元的变性坏死。随着研究的深入,发现细胞自噬介导病理性α-Syn的清除过程参与PD的发病过程。自噬是细胞清除异常聚集蛋白和衰老受损细胞器的重要途径,自噬清除α-Syn异常沉积可维持细胞稳态,保护多巴胺能神经元。此外,自噬过程受损引起α-Syn聚集,增加α-Syn在脑内的传播,促进多巴胺能神经元退变,参与到PD的发生发展中。PD相关基因影响自噬调控,PD相关基因突变能导致溶酶体功能受损进而阻断自噬。同时异常聚集的α-Syn会进一步破坏自噬过程,降低自噬清除能力,增加神经毒性累积。自噬受损和α-Syn异常聚集是黑质多巴胺能神经元退行性变的重要机制。因此,针对自噬和α-Syn异常聚集的研究可为PD的发病机制提供新的思路,通过增加自噬通量,减少α-Syn积累可能成为治疗PD的重要靶点。

Parkinson disease(PD)is a common chronic neurodegenerative disease that seriously affects the quality of life of patients and has become an important population health problem in society.The typical neuropathological feature of PD is the abnormal aggregation ofα-synuclein(α-Syn)in the substantia nigra-striatal region,causing dopaminergic degenerative necrosis of neurons.With further research,it was found that cellular autophagy mediated the clearance process of pathologicalα-Syn involved in the pathogenesis of PD.Autophagy is an important pathway for cells to remove abnormal aggregated proteins and senescence-damaged organelles,and autophagic removal of abnormalα-Syn deposition can maintain cellular homeostasis and protect dopaminergic neurons.In addition,impaired autophagy causesα-Syn aggregation,increasesα-Syn propagation in the brain,promotes the degeneration of dopaminergic neurons,and is involved in the development of PD.PD-related genes affect autophagy regulation,and mutations in related genes can lead to impaired lysosomal function to block autophagy.At the same time,abnormal aggregation ofα-Syn further disrupts the autophagy process,reduces the autophagic clearance capacity,and increases the accumulation of neurotoxicity.Impaired autophagy and abnormalα-Syn aggregation are important mechanisms of degeneration in nigrostriatal dopaminergic neurons.Therefore,studies targeting autophagy and abnormalα-Syn aggregation may provide new ideas for the pathogenesis of PD,and reducingα-Syn accumulation by increasing autophagic flux may become a key target for the treatment of PD.