Proteinaceous aggregates containing
alpha-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
alpha-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
alpha-synuclein aggregates was investigated. Purified tTGase catalyzed
alpha-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
alpha-synuclein aggregates in cellular models. Immunocytochemical studies demonstrated the presence of
alpha-synuclein-positive cytoplasmic inclusions in 8% of tTGase-expressing cells. The formation of these aggregates was significantly augmented by the
calcium ionophore and prevented by the inhibitor
cystamine. Immunohistochemical studies on postmortem brain tissue confirmed the presence of
transglutaminase-catalyzed
epsilon (gamma-glutamyl)lysine cross-links in the halo of Lewy bodies in
Parkinson's disease and
dementia with Lewy bodies, colocalizing with
alpha-synuclein. These findings, taken together, suggest that tTGase activity leads to
alpha-synuclein aggregation to form Lewy bodies and perhaps contributes to neurodegeneration.