Absract  alpha-Synuclein is mutated in Parkinson's disease (PD) and is found in cytosolic inclusions, called Lewy bodies, in sporadic forms of the disease. A fraction of alpha-synuclein purified from Lewy bodies is monoubiquitinated, but the role of this monoubiquitination has been obscure.We now review recent data indicating a role of alpha-synuclein monoubiquitination in Lewy body formation and implicating the autophagic pathway in regulating these processes. The E3 ubiquitin-ligase SIAH is present in Lewy bodies and monoubiquitinates alpha-synuclein at the same lysines that are monoubiquitinated in Lewy bodies. Monoubiquitination by SIAH promotes the aggregation of alpha-synuclein into amorphous aggregates and increases the formation of inclusions within dopaminergic cells. Such effect is observed even at low monoubiquitination levels, suggesting that monoubiquitinated alpha-synuclein may work as a seed for aggregation. Accumulation of monoubiquitinated alpha-synuclein and formation of cytosolic inclusions is promoted by autophagy inhibition and to a lesser extent by proteasomal and lysosomal inhibition. Monoubiquitinated alpha-synuclein inclusions are toxic to cells and recruit PD-related proteins, such as synphilin-1 and UCH-L1. Altogether, the new data indicate that monoubiquitination might play an important role in Lewy body formation. Decreasing alpha-synuclein monoubiquitination, by preventing SIAH function or by stimulating autophagy, constitutes a new therapeutic strategy for Parkinson's disease.

   帕金森病(PD)中alpha-synuclein突变，在散发型帕金森病的细胞溶质内涵物(称为Lewy体)中alpha-synuclein同样被发现。从Lewy体纯化出的alpha-synuclein一个成份为单泛素化的，但是此单泛素化的作用仍不清楚。我们现在回顾新近的资料，揭示alpha-synuclein单泛素化在Lewy体形成中的作用以及涉及调节这些过程的自噬途径。E3泛素联接酶SIAH存在于Lewy体并且在相同的赖胺酸alpha-synuclein单泛素化，也就是说在Lewy体中是单泛素化的。通过SIAH单泛素化促进了alpha-synuclein聚集为不规则聚集体，从而在多巴胺能细胞内形成内涵物。即使在低单泛素化水平也可观察到这样的作用,提示alpha-synuclein单泛素化可能起聚集种子的作用。通过抑制自噬以及通过抑制蛋白酶体和溶酶体可达到更低的程度，从而促进单泛素化alpha-synuclein的积聚和细胞溶质内涵物的形成。单泛素化alpha-synuclein内涵物具有细胞毒性并且募集PD相关蛋白质,比如synphilin-1以及UCH-L1。总而言之,新近数据表明单泛素化在Lewy体形成中起重要作用，通过阻止SIAH功能或者通过刺激自噬降低alpha-synuclein单泛素化成为帕金森病一个新的治疗学方法。