期刊
AUTOPHAGY
卷 4, 期 3, 页码 372-374出版社
LANDES BIOSCIENCE
DOI: 10.4161/auto.5604
关键词
parkinson's disease; Lewy bodies; alpha-synuclein; autophagy; monoubiquitination; inclusion bodies; synphilin-1
类别
alpha-synudein 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 (x-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 doparninergic cells. Such effect is observed even at low monoubiquitination levels, suggesting that monoubiquitinated alpha-synudein 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-synudein monoubiquitination, by preventing SIAH function or by stimulating autophagy, constitutes a new therapeutic strategy for Parkinson's disease.
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