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Pro‐apoptotic protein glyceraldehyde‐3‐phosphate dehydrogenase promotes the formation of Lewy body‐like inclusions
Author(s) -
Tsuchiya Katsumi,
Tajima Hisao,
Kuwae Toyoyasu,
Takeshima Takao,
Nakano Toshiya,
Tanaka Masaharu,
Sunaga Katsuyoshi,
Fukuhara Yoko,
Nakashima Kenji,
Ohama Eisaku,
Mochizuki Hideki,
Mizuno Yoshikuni,
Katsube Nobuo,
Ishitani Ryoichi
Publication year - 2005
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2005.03870.x
Subject(s) - glyceraldehyde 3 phosphate dehydrogenase , lewy body , biology , apoptosis , mutant , microbiology and biotechnology , inclusion bodies , cytoplasmic inclusion , parkinson's disease , cytoplasm , messenger rna , pathology , gene , biochemistry , recombinant dna , medicine , disease
Glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) has long been recognized as a classical glycolytic protein; however, previous studies by our group and others have demonstrated that GAPDH is a general mediator initiating one or more apoptotic cascades. Our most recent findings have elucidated that an expression of a pro‐apoptotic protein GAPDH is critically regulated at the promoter region of the gene. Apoptotic signals for its subsequent aggregate formation and nuclear translocation are controlled by the respective functional domains harboured within its cDNA component. In this study, coexpression of GAPDH with either wild‐type or mutant (A53T) α‐synuclein and less likely with β‐synuclein in transfected COS‐7 cells was found to induce Lewy body‐like cytoplasmic inclusions. Unlike its full‐length construct, the deleted mutant GAPDH construct (C66) abolished these apoptotic signals, disfavouring the formation of inclusions. The generated inclusions were ubiquitin‐ and thioflavin S‐positive appearing fibrils. Furthermore, GAPDH coimmunoprecipitated with wild‐type α‐synuclein in this paradigm. Importantly, immunohistochemical examinations of post mortem materials from patients with sporadic Parkinson's disease revealed the colocalized profiles immunoreactive against these two proteins in the peripheral zone of Lewy bodies from the affected brain regions (i.e. locus coeruleus). Moreover, a quantitative assessment showed that about 20% of Lewy bodies displayed both antigenicities. These results suggest that pro‐apoptotic protein GAPDH may be involved in the Lewy body formation in vivo, probably associated with the apoptotic death pathway.