Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase

Beena Koshy, Toni Matilla, Eric N. Burright, Diane E. Merry, Kenneth H. Fischbeck, Harry T. Orr, Huda Y. Zoghbi

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Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative disorders caused by expansions of translated CAG trinucleotide repeats which code for polyglutamine in the respective proteins. Most hypotheses about the molecular defect in these disorders suggest a gain of function, which may involve interactions with other proteins via the expanded polyglutamine tract. In this study we used ataxin-1, the SCA1 gene product, as a bait in the yeast two-hybrid system and identified the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase as an ataxin-1 interacting protein. In addition, the yeast two hybrid data demonstrate that wild type and mutant ataxin-1 form home and heterodimers. Physical interaction between GAPDH and ataxin-1 was also demonstrated in vitro. To investigate if GAPDH might interact with other glutamine repeat-containing proteins involved in neurodegenerative disorders, we tested its binding to the androgen receptor which is mutated in spinobulbar muscular atrophy. The androgen receptor interacts with GAPDH both in the yeast two-hybrid system and in vitro. The binding of both ataxin-1 and the androgen receptor to GAPDH does not vary with the length of the polyglutamine tract. While provocative, these findings do not address the selective neuronal loss in each of these disorders in light of the wide expression patterns of GAPDH and the respective polyglutamine containing proteins. Nonetheless, such interactions may increase the susceptibility of specific neurons to a variety of insults and initiate degeneration.

Original languageEnglish (US)
Pages (from-to)1311-1318
Number of pages8
JournalHuman molecular genetics
Issue number9
StatePublished - Sep 1996

Bibliographical note

Funding Information:
We thank Drs S. Elledge and W.J. Harper for vectors, yeast strains and control bait plasmids; E.N. Olson and Q. Ling for the mouse embryonic cDNA library; D. Beach for the HF7c yeast strain; E.M. Wilson for the AR COS7 constructs and A. Brinkmann for the mAb to the AR. B.K. thanks M. Edwards, A. McCall and M. Bhat for helpful discussions. This work was supported by grants from the National Institutes of Health Grants (NS27699) to H.Y.Z., (NS22920) to H.T.O., (NS32214) to K.H.F. and (NS09724) to E.N.B. and from the Muscular Dystrophy Association to K.H.F. and D.E.M. H.Y.Z. is an investigator with the Howard Hughes Medical Institute. T. Matilla is supported by the Spanish Ministerio de Educación y Ciencia (PF94 968798). Portions of this work were supported by core facilities of the Mental Retardation Research Center and the Child Health Research Center at Baylor College of Medicine.


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