标题：Tissue transglutaminase-induced aggregation of α-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：4
页码：2047-2052
DOI：10.1073/pnas.0438021100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Proteinaceous aggregates containing -synuclein represent a feature of neurodegenerative disorders such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Despite extensive research, the mechanisms underlying -synuclein aggregation remain elusive. Previously, tissue transglutaminase (tTGase) was found to contribute to the generation of aggregates by cross-linking pathogenic substrate proteins in Huntington's and Alzheimer's diseases. In this article, the role of tTGase in the formation of -synuclein aggregates was investigated. Purified tTGase catalyzed -synuclein cross-linking, leading to the formation of high molecular weight aggregates in vitro, and overexpression of tTGase resulted in the formation of detergent-insoluble -synuclein aggregates in cellular models. Immunocytochemical studies demonstrated the presence of -synuclein-positive cytoplasmic inclusions in 8% of tTGase-expressing cells. The formation of these aggregates was significantly augmented by the calcium ionophore A23187 and prevented by the inhibitor cystamine. Immunohistochemical studies on postmortem brain tissue confirmed the presence of transglutaminase-catalyzed {varepsilon}({gamma}-glutamyl)lysine cross-links in the halo of Lewy bodies in Parkinson's disease and dementia with Lewy bodies, colocalizing with -synuclein. These findings, taken together, suggest that tTGase activity leads to -synuclein aggregation to form Lewy bodies and perhaps contributes to neurodegeneration.
