Role of CA-repeats microsatellites in TDP-43 and FUS linked neurodegenerative diseases – CA-Ts

Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) are fatal neurodegenerative diseases characterized by accumulations of TDP-43 and FUS, two proteins selectively binding to RNAs enriched in GU, transcribed from CA-rich sequences. Our recent results show CA-repeats, enriched in brain-specific genes, are methylated and recognized by p70, a binding partner of TDP-43 and FUS. Here we hypothesize that methylation of CA-repeats is coordinated with p70 binding and with TDP-43 and FUS recruitment on corresponding pre-mRNAs, to modulate key neuronal genes. We will determine the disease relevance of the TDP-43/FUS/p70/CA-repeats pathway using neuronal cell cultures, mouse and patients-derived tissues, and genome-wide technologies focusing on adult neurons. Pathophysiological relationships will be determined by knocking down or overexpressing p70 in a mouse model knock for a FUS mutation to characterize the potential therapeutic effect. This project will provide the relevance of p70 pathway to ALS/FTD and define therapeutic targets for these fatal neurodegenerative diseases.