Interplay of RAN translation and FMRP synthesis in Fragile X‐associated disorders

Abstract

Fragile X syndrome, the most common monogenic form of intellectual disability, arises from large CGG repeat expansions in the 5’UTR of FMR1 which preclude production of the Fragile X protein, FMRP. Moderate (55-200) CGG repeat expansions in this same gene permit FMRP production but cause the clinically distinct neurodegenerative disorder Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). In FXTAS, these repeats elicit neurotoxicity in part through repeat associated non-AUG (RAN) translation of toxic homo-polymeric proteins. Previously, we demonstrated that RAN translation plays a native role in regulating the translation of FMRP in neurons by acting as an upstream open reading frame. However, the mechanism by which this regulation occurs remained unclear. In this study, we investigate the interplay between RAN translation and FMRP initiation. Intriguingly, both RAN translation and FMRP synthesis can occur through cap-dependent and cap-independent mechanisms, with marked differences observed between cell types and cell states. This cap-independent translation is influenced by repeat length and RAN translation reading frame. Ongoing studies are characterizing how these cap-independent mechanisms and RAN translation contribute to the regulation of FMRP synthesis in neurons in response to stimuli that elicit neuronal plasticity.