Substrates for Transglutaminase-Catalyzed Cross-Linking: Relevance to Pathogenesis of Huntington’s Disease and Chorea-Acanthocytosis

Protein aggregates are a hallmark of polyglutamine diseases, including Huntington’s disease (HD). The transglutaminases, a class of Ca2+-dependent cross-linking enzymes, could be directly involved in the disease mechanisms [14,15]. In fact, we have shown that when tTGase is activated by a calcium ionophore, the expanded huntingtin fragment is more abundant and insoluble high molecular weight (Mw) aggregates in HD fibroblasts appear together with evidence of apoptosis. Interestingly, in chorea-acanthocytosis (ChAc) a rare autosomal-recessive disorder without CAG repeats, we found increased amounts of tTGase products in muscle and erythrocytes. Furthermore, immunohistochemistry demonstrated abnormal accumulation of tTGase products, as well as of proteinaceous bodies in ChAc muscles.