Abnormal modification of alpha-synuclein and its mechanism in Parkinson's disease / 中国组织工程研究

ABSTRACT

BACKGROUND:The formation of Lewy bodies due to abnormal α-synuclein aggregation is a characteristic pathological change in Parkinson's disease.In recent years,several studies have revealed that the formation of α-synuclein aggregates is closely related to its post-translational modifications.The modification of α-synuclein such as phosphorylation,nitration,acetylation,and ubiquitination has attracted extensive attention in the pathogenesis and progression of Parkinson's disease. OBJECTIVE:To review the research progress in the effect of modification types and sites of α-synuclein on the characteristic pathological formation and progression of Parkinson's disease. METHODS:PubMed and CNKI databases were searched by the first author with the key words of"α-synuclein,Parkinson's disease,phosphorylation,acetylation,ubiquitination,nitration"in English and Chinese respectively to collect and sort out the literature related to abnormal modification of α-synuclein in recent years.Finally,61 articles were included for further review. RESULTS AND CONCLUSION:Abnormal modification of α-synuclein is closely related to its protein structure and its positive and negative charges.Its amino terminus is positively charged and prone to ubiquitination and acetylation modifications.The central hydrophobic region is prone to forming β-pleated sheet due to its hydrophobic property.The carboxyl terminus is negatively charged,which is the main phosphorylation modification region.Phosphorylation modification sites promote phosphorylation modification and are closely related to α-synuclein aggregation,while protein kinases can target the activation of translational modifications,which may help to promote or inhibit aggregate formation.The degradation pathway of α-synuclein mainly plays a role in removing pathological proteins.Various kinase catalysts contribute to impaired protein ubiquitination modifications that lead to abnormal protein accumulation,thereby exacerbating neurodegeneration.The amino-terminal acetylation of α-synuclein improves the shuttle ability of the protein to the cell membrane and slows down the protein aggregation,which may be the protection target of nerve cells.However,the acetylation modification of the mutant protein produces the opposite effect.The protein nitration modification is mainly related to oxidative stress.The aggregation tendency of the protein modified by nitration is enhanced under the action of reactive oxygen species.Different post-translational modifications have different effects.Therefore,elucidating the main mechanisms of their post-translational modifications and inhibiting the post-translational modifications that contribute to protein aggregation may provide a reference for new targets for early diagnosis and treatment of Parkinson's disease.