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

Published

Journal Article

Several adult-onset neurodegenerative diseases are caused by genes with expanded CAG triplet repeats within their coding regions and extended polyglutamine (Qn) domains within the expressed proteins. Generally, in clinically affected individuals n >/= 40. Glyceraldehyde 3-phosphate dehydrogenase binds tightly to four Qn 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 Qn domain of pathological length (n = 62 or 81). The dehydrogenase is less strongly inhibited by tissue transglutaminase in the presence of constructs containing shorter Qn domains (n = 0 or 10). Purified alpha-ketoglutarate dehydrogenase complex also is inactivated by tissue transglutaminase plus glutathione S-transferase constructs containing pathological-length Qn 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/Qn expansion diseases.

Full Text

Duke Authors

Cited Authors

  • Cooper, AJ; Sheu, KR; Burke, JR; Onodera, O; Strittmatter, WJ; Roses, AD; Blass, JP

Published Date

  • November 11, 1997

Published In

Volume / Issue

  • 94 / 23

Start / End Page

  • 12604 - 12609

PubMed ID

  • 9356496

Pubmed Central ID

  • 9356496

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.94.23.12604

Language

  • eng

Conference Location

  • United States