Contributors to FXTAS Progression

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SUMMARY Carriers of the FMR1 premutation have expanded CGG repeats at the 5’ UTR of this gene. Carriers have a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disease accompanied by tremor and ataxia as well as deficits in cognition, learning, and other neuropsychological issues (depression, anxiety). Neurodegeneration in FXTAS is accompanied by increased oxidative stress, lower mitochondrial bioenergetic capacity, limited unfolded protein response and a poorly characterized neuroinflammatory process. Surprisingly, not all carriers of the premutation develop FXTAS and the progression from milder to more detrimental stages is highly variable even in subjects with comparable age. As of today, there is no cure for FXTAS or to prevent its development. Exosomes are proposed to mediate pathophysiological signaling in a variety of target cells and their concentration spike in diseases associated with inflammation. Here, we hypothesize that circulating exosomes with detrimental cargoes are contributors to the onset and/or the progression of the disease. To this end, we will characterize exosomes from plasma obtained from sex- and age-matched noncarriers, carriers with and without FXTAS. The thorough characterization will entail evaluation of number and size, miRNA, and protein profiling. The characterization will serve as a platform to identify qualitative and quantitative differences as well as to identify the involvement of different biological pathways. The putative “toxic” effect of exosomes derived from carriers with and without FXTAS will be assessed by evaluating the bioenergetics of target cells (neurons and glia). These studies will provide an insight on the mechanism underlying the impact of exosomal components to the onset of mitochondrial dysfunction (as it is observed in carriers with FXTAS) and the progression of ataxia and tremors, key features of FXTAS-affected subjects.