Polyglutamine Domains Are Substrates of Tissue Transglutaminase: Does Transglutaminase Play a Role in Expanded CAG/Poly‐Q Neurodegenerative Diseases?

: Huntington's disease and six other neurodegenerative diseases are associated with abnormal gene products containing expanded polyglutamine (poly‐Q; Qn) domains (n ≥ 40). In the present work, we show that glutathione S‐transferase (GST) fusion proteins containing a small, physiological‐length poly‐Q domain (GSTQ10) or a large, pathological‐length poly‐Q domain (GSTQ62) are excellent substrates of guinea pig liver (tissue) transglutaminase and that both GSTQ10 and GSTQ62 are activators of tissue transglutaminase‐catalyzed hydroxaminolysis of N‐α‐carbobenzoxyglutaminylglycine. The present findings have implications for understanding the pathophysiological mechanisms of expanded CAG/poly‐Q domain diseases.