Identify a therapy strategy for FXTAS – DrugFXTAS

Fragile X-associated tremor/ ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder characterized by progressive intention tremor, gait ataxia and cognitive decline. Nearly 1 in 4000 adult male has a lifetime risk of developing FXTAS, which make of FXTAS one of the most common single gene causes of tremor, ataxia and cognitive decline. Importantly, FXTAS shares some common features with other neurodegenerative diseases, such as Parkinson disease.

FXTAS is caused by an expansion of 55 to 200 CGG repeats in the 5’-UTR of the FMR1 gene. Other and we found that expanded CGG repeats are translated into a toxic protein, FMRpolyG, in absence of any ATG start codon. Instead, CGG repeats are translated through initiation to an ACG near cognate initiation codon located upstream of the repeats (Sellier et al., 2017). However, it is currently unclear how FMRpolyG is leading to neuronal cell dysfunctions an ultimately cell death in FXTAS. Furthermore, there is no treatment for this devastating disease. Thus, I propose to:

1 - Explore by which molecular and cellular mechanisms FMRpolyG is toxic.
2 - Identify pharmacological compounds correcting cell death due to FMRpolyG.

This proposal will help to clarify the pathogenic mechanisms of CGG repeats toxicity in FXTAS, a first and necessary step to identify relevant biomarkers and define therapeutic strategies for this devastating disease.