Tissue Transglutaminase-Induced Aggregation of α-Synuclein: Implications for Lewy Body Formation in Parkinson's Disease and Dementia with Lewy Bodies

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 4; pp. 2047 - 2052
• Main Authors: Junn, Eunsung, Ronchetti, Ruben D., Quezado, Martha M., Kim, Soo-Youl, Mouradian, M. Maral
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.02.2003; National Acad Sciences; The National Academy of Sciences
• Subjects: Aggregation; alpha-Synuclein; Animals; Antibodies; Base Sequence; Biological Sciences; Calcium; Cell aggregates; Cell Line; COS cells; Dementia; Dementia - enzymology; Dementia - metabolism; Dementia - pathology; DNA Primers; Enzymes; Humans; Immunohistochemistry; Lewy bodies; Lewy Bodies - pathology; Nerve Tissue Proteins - metabolism; Parkinson disease; Parkinson Disease - enzymology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathogenesis; Proteins; Synucleins; Transglutaminases - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0438021100

Proteinaceous aggregates containing α-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 α-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 α-synuclein aggregates was investigated. Purified tTGase catalyzed α-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 α-synuclein aggregates in cellular models. Immunocytochemical studies demonstrated the presence of α-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 ε(γ-glutamyl)-lysine cross-links in the halo of Lewy bodies in Parkinson's disease and dementia with Lewy bodies, colocalizing with α-synuclein. These findings, taken together, suggest that tTGase activity leads to α-synuclein aggregation to form Lewy bodies and perhaps contributes to neurodegeneration.