Fundamental mechanisms of translation of Tau mRNA in Alzheimer Disease – RiboTAUxic

Protein translation is a complex and highly regulated multi-step process that requires numerous factors and relies on mRNAs sequence and structure. Dysfunctions in translation initiation often occur under stress conditions and are associated with human diseases. In the case of Alzheimer's disease, some neuronal stress such as inflammation and amyloid deposits could trigger translation deregulation. In Alzheimer's disease, as well as in other related neurodegenerative diseases termed Tauopathies, Tau proteins aggregates are the hallmarks of degenerating neurons. The mechanisms leading to Tau pathology are not yet elucidated. Among Tau species found in Alzheimer's disease brains, truncated variants of the Tau proteins are probably involved in pathological process. We have recently uncovered new Tau protein variant that is only detected in Alzheimer's disease patients. Our preliminary data indicate that this new variant is found early in the course of neurodegeneration and could have an etiological role in Alzheimer's disease. Also, this Tau variant is not generated through not proteolysis, the mechanism that is so far described for generation of truncated variants of Tau proteins, but rather from an alternative translation initiation event. The present project aims to explore new hypotheses about Alzheimer’s disease etiopathology. Our original working hypothesis, based on solid preliminary data, is that this new Tau variant results from an alternative AUG start site in tau mRNA and therefore dysfunctions in translation initiation are likely involved in Alzheimer's disease pathophysiological process. Our project will focus on deciphering fundamental aspects of alternative translation initiation mechanisms that lead to the synthesis of the new Tau variant and their pathophysiological relevance to Alzheimer's disease. In the framework of this project, we will pursue several goals. First, using state-of-the-art molecular methodologies, we will elucidate the translation-related mechanisms underlying tau alternative initiation site. Thanks to relevant cellular and mouse models of Tau pathology as well as human brain tissues, we will investigate how these mechanisms occur in Alzheimer's disease and their role pathological process. Also, our project will pave the way for new therapeutic options in Alzheimer's disease and related Tauopathies. In conclusion, our recent discovery of a new Tau variant and of an alternative site for the Tau protein translation sustains the rationale of the present highly original project that will tackle, thanks to the strong added-value synergy between the two partners, the role of translation factors in Tau pathology by complementary and non-redundant approaches. The project will be achieved by the unique combination of knowledge and methodologies developed by both partners on the field of mRNAs structure and translation mechanisms, and in the field of Tau biology and Tauopathies.