Contribution of tRNA fragments in the ETiopathogenesis of Huntington's Disease (tR-GET HD)

ended

Many pathogenic mechanisms are involved in Huntington’s disease (HD), the most prevalent monogenic neurological disease in Europe, with no current cure. The host team reported a dysregulation of tRNA-fragments (tRFs) in HD brains; other studies showed higher stress granules' (SG) density in HD, and that tRFs promote SG assembly. Thus, my hypothesis is that HD-related tRFs contribute to the accumulation of SG, initiating mutant huntingtin (mtHTT) aggregation and leading to disease pathogenesis. I propose to explore the interaction between mtHTT aggregates, and tRFs and SG, as new potential therapeutic targets. Specifically, I aim to study the 1) cell-type specificity of tRFs formation and their correlation with HD progression; 2) molecular mechanisms by which tRFs may induce HD pathology; and 3) potential of tRFs modulators to treat mtHTT-related neurotoxicity. This project’s success relies on the perfect synergy of the host team’s expertise in tRFs biology and HD and my own experience in RNA and proteotoxicity in neurodegenerative diseases, thoroughly addressing the hypothesis via complementary human, cellular and mice HD models and a plural array of bioinformatic, molecular biology and genomic approaches. The outcomes will help define the role of tRFs and SG in mtHTT aggregation, and may be used as preclinical proof-of-concept for novel HD therapies, reflecting the project’s translational potential. I will benefit from scientific exchanges with expert neuroscientists in the host institution, particularly my supervisor, whose skills in functional genomics fully match my expertise in RNA and protein pathological mechanisms. My translational technical knowledge and network of collaborators will be useful to the host group to build new cooperative projects. Thus, the MSCA fellowships will allow me to develop unique technical and transferable skills, helping me progress and establish myself as a leader in neurodegenerative research within a European research institute.