Potential Role of Tazarotene-Induced Gene 3 and Transglutaminase 1 in Tauopathies

Abstract

The family of neurodegenerative diseases, called tauopathies, includes Alzheimer's disease, progressive supranuclear palsy, and Pick's disease. These diseases are associated with the formation of tau inclusions and neuronal cell death. Tau inclusions are characterized by the presence of neurofibrillary tangles (NFTs), where protein Tau, a member of microtubule-associated proteins (MAPs), is found to be, hyperphosphorylated and aggregated. The formation of these aggregates leads to microtubule instability and cellular toxicity. There are several lines of evidence that demonstrate this aggregation is due to transglutaminase mediated cross-linking of Tau protein. However, little is known about the mechanism of the hyperphosphorylation, aggregation and tau-associated toxicity. Analysis of brains with tau pathologies showed the colocalized expression of transglutaminase 1 (TG1) and its activator, tazarotene-induced gene 3 (TIG3) in NFTs, suggesting functional relevancy. Hereby, we hypothesized that TIG3 regulates TG1-catalysed cross-linking of Tau, and therefore the formation of Tau inclusions in neurons. To test this hypothesis, neurons differentiated from human embryonic stem cells used to develop an in-vitro tauopathy model. Endogenous expression analyses of TIG3, TG1 and Tau were performed and induction of Tau occlusions via overexpression of TIG3 studied. Results have shown endogenous TIG3 mRNA and protein were expressed in neurons derived from embryonic stem cells. Endogenous TIG3, TG1 and TAU have shown colocalization. Cells overexpressing TIG3 have shown a higher level of colocalization and increased Tau aggregation, which confirmed our hypothesis. The results of this study provide new mechanistic insights into the formation of neurofibrillary tangles and the resulting pathology.