Transglutaminase 2 in neurodegenerative disorders

Type 2 transglutaminase (TG2) is a calcium-dependent acyltransferase which also undergoes a GTP-binding/GTPase cycle even though it lacks any obvious sequence similarity with canonical GTP-binding (G) proteins. As an enzyme which is responsible for the majority of transglutaminase (TG) activity in the brain, TG2 is likely to play a modulatory role in nervous system development and has regulatory effect on neuronal cell death as well. Most importantly, numerous studies have presented data demonstrating that dysregulation of TG2 may contribute to the pathogenesis of many neurodegenerative disorders, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis as well as nervous system injuries. Although TG2's involvement in these disease conditions is strongly suggested by various findings, such as the increase of TG2 mRNA expression, protein level and TG activity in the pathological process of these neurodegenerative disorders, as well as the therapeutic effect of TG2 genetic deletion in animal models of Huntington's disease, the precise mechanism underlying TG2's role remain unclear. TG2 was originally proposed to contribute to the pathogenesis of these diseases by facilitating the formation of insoluble protein aggregates, however recent findings clearly indicate that this is likely not the case. Nonetheless, there is data to suggest that TG2 may play a role in neurodegenerative processes by stabilizing toxic oligomers of the disease-relevant proteins, although further studies are needed to validate these initial in vitro findings.