Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and α-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length

Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and α-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length

Departments of ^*Biochemistry, ^†Neurology and Neuroscience, and ^‡‡Medicine, Cornell University Medical College, New York, NY 10021; ^‡Burke Medical Research Institute, Cornell University Medical College, White Plains, NY 10605; and Departments of ^¶Medicine, ^**Neurobiology, and ^‖Deane Laboratory, Duke University Medical Center, Durham, NC 27710

Edited by Louis Sokoloff, National Institutes of Health, Bethesda, MD, and approved August 28, 1997 (received for review April 24, 1997)

Abstract

Several adult-onset neurodegenerative diseases are caused by genes with expanded CAG triplet repeats within their coding regions and extended polyglutamine (Q_n) domains within the expressed proteins. Generally, in clinically affected individuals n ≥ 40. Glyceraldehyde 3-phosphate dehydrogenase binds tightly to four Q_n disease proteins, but the significance of this interaction is unknown. We now report that purified glyceraldehyde 3-phosphate dehydrogenase is inactivated by tissue transglutaminase in the presence of glutathione S-transferase constructs containing a Q_n domain of pathological length (n = 62 or 81). The dehydrogenase is less strongly inhibited by tissue transglutaminase in the presence of constructs containing shorter Q_n domains (n = 0 or 10). Purified α-ketoglutarate dehydrogenase complex also is inactivated by tissue transglutaminase plus glutathione S-transferase constructs containing pathological-length Q_n domains (n = 62 or 81). The results suggest that tissue transglutaminase-catalyzed covalent linkages involving the larger poly-Q domains may disrupt cerebral energy metabolism in CAG/Q_n expansion diseases.

Footnotes

↵ § To whom reprint requests should be addressed at: Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605. e-mail: ajlc{at}mail.med.cornell.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: CoASH, coenzyme A; CGG, N-α-carbobenzoxyglutaminylglycine; GAP, glyceraldehyde 3-phosphate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GST, glutathione S-transferase; HD, Huntington disease; KGDHC, α-ketoglutarate dehydrogenase complex; Q_n, polyglutamine; SCA, spinocerebellar ataxia; tTGase, tissue transglutaminase.