TRANSGLUTAMINASE-CATALYZED INACTIVATION OF GLYCERALDEHYDE-3-PHOSPHATEDEHYDROGENASE AND ALPHA-KETOGLUTARATE DEHYDROGENASE COMPLEX BY POLYGLUTAMINE DOMAINS OF PATHOLOGICAL LENGTH

Several adult-onset neurodegenerative diseases are caused by genes wit h expanded CAG triplet repeats within their coding regions and extende d polyglutamine (a) domains within the expressed proteins. Generally, in clinically affected individuals n greater than or equal to 40. Glyc eraldehyde 3-phosphate dehydrogenase binds tightly to four Q(n) diseas e proteins, but the significance of this interaction is unknown. We no w report that purified glyceraldehyde 3-phosphate dehydrogenase is ina ctivated by tissue transglutaminase in the presence of glutathione S-t ransferase constructs containing a a domain of pathological length (n = 62 or 81). The dehydrogenase is less strongly inhibited by tissue tr ansglutaminase in the presence of constructs containing shorter Q(n) d omains (n = 0 or 10). Purified cr-ketoglutarate dehydrogenase complex also is inactivated by tissue transglutaminase plus glutathione S-tran sferase constructs containing pathological-length a domains (n = 62 or 81). The results suggest that tissue transglutaminase-catalyzed coval ent linkages involving the larger poly-Q domains may disrupt cerebral energy metabolism in CAG/Q(n) expansion diseases.