Tissue transglutaminase-induced aggregation of alpha-synuclein: Implications for Lewy body formation in Parkinson's disease and dementia with Lewy bodies.
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.
Junn
Eunsung
E
Genetic Pharmacology Unit, Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1406, USA.
Ronchetti
Ruben D
RD
Quezado
Martha M
MM
Kim
Soo-Youl
SY
Mouradian
M Maral
MM
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D003704:Dementia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051843:Synucleins; D011503:Transglutaminases / Q000378:metabolism*; D051844:alpha-Synuclein
D017931:DNA Primers; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D011503:Transglutaminases