ToFU

Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) are two fatal adult-onset neurodegenerative diseases with a lifetime risk of 1/1000. Both ALS and FTD patients share a very poor prognosis and limited treatment options. ALS and FTD share common genetic risk factors, and co-occur in families and/or in individual patients. A subset of ALS cases (10-20%) is inherited, and referred to as familial ALS or FTD. Three mutually exclusive neuropathological inclusions are found in ALS/FTD patients: cytoplasmic inclusions of TDP-43 (TDP-43 proteinopathy), FUS (FUSopathy) or TAU proteins (so-called TAUopathy). TDP-43 and FUS are RNA-binding proteins involved in multiple steps of RNA metabolism, from transcription to alternative splicing and transport. TAU protein is a cytoskeletal protein that is critical for the stability of microtubule structure and functions in neurons. Further strengthening the role of these three proteins in ALS/FTD, mutations in TDP-43 and FUS genes have been identified in fALS and mutations in TAU are associated with a significant proportion of familial FTD. In all, pathology and genetics converge to ascribe a predominant pathogenic role for TDP-43, TAU and FUS in the development of ALS/FTD. Defining the mechanistic relationships between TDP-43, FUS and TAU is the subject of the current application. Mechanistic relationships between TAU and FUS have been described, and our consortium has available both mouse models and zebrafish models of Fus and Tau mediated diseases. Thus, we will focus our work on the TAU/FUS epistatic interaction and our major objective is to evaluate the contribution of FUS to TAUopathies, and of TAU to FUSopathies. In parallel, we will explore possible interactions between TAU and TDP-43 mostly in zebrafish models. Likewise, we will also extend our analysis to other RNA-binding proteins such as ATXN2, TAF15 and EWSR1 in zebrafish models. We propose to answer to three complementary yet independent scientific questions: Aim 1) Does cytoplasmic mislocalization of FUS alter TAU metabolism and trigger FTD? Aim 2) Are TAUopathies associated with altered function or localisation of FUS or TDP-43? Aim 3) Does TAU contribute to neurodegeneration due to mutations in FUS, TDP-43 and in other RNA-binding proteins? The originality of our project lies in different aspects. First, we have been using gene targeting, rather than classical transgenesis for generating our mouse models. We think this will likely lead to very relevant insights into disease mechanisms. Second, our experimental approach is multi-organismal, from zebrafish and mouse models to human patients. Third, our project is seeking to delineate a coherent pathogenic pathway for currently unrelated FTD causes. Overall, we believe that this proposal has the potential to impact durably our understanding of ALS and FTLD pathogenesis by using unique animal models to identify cell type specific alterations, validate these alterations in the human tissue which together will represent novel and valuable therapeutic targets.