TY - JOUR T1 - Disentangling the sequence, cellular and ultrastructural determinants of Huntingtin nuclear and cytoplasmic inclusion formation JF - bioRxiv DO - 10.1101/2020.07.29.226977 SP - 2020.07.29.226977 AU - Nathan Riguet AU - Anne-Laure Mahul-Mellier AU - Niran Maharjan AU - Johannes Burtscher AU - Alice Patin AU - Marie Croisier AU - Graham Knott AU - Veronika Reiterer AU - Hesso Farhan AU - Hilal A. Lashuel Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/30/2020.07.29.226977.abstract N2 - Despite the strong evidence linking the aggregation of the Huntingtin protein (Htt) to the pathogenesis of Huntington’s disease (HD), the mechanisms underlying Htt aggregation and neurodegeneration remain poorly understood. Herein, we investigated the ultrastructural properties and protein composition of Htt inclusions in cells overexpressing mutant exon1 of the Htt protein. Our findings provide novel insight into the ultrastructural properties of cytoplasmic and nuclear Htt inclusions and their mechanisms of formation. We show that Htt inclusion formation and maturation are complex processes that, although initially driven by polyQ-dependent Htt aggregation, also involve 1) polyQ and PRD domain-dependent sequestration of lipids and cytoplasmic and cytoskeletal proteins related to HD dysregulated pathways; 2) recruitment and accumulation of remodeled or dysfunctional membranous organelles; and 3) impairement of the protein quality control and degradation machineries. Interestingly, nuclear and cytoplasmic Htt inclusions exhibited distinct biochemical composition and ultrastructural properties, suggesting different formation mechanisms and toxicity.Graphical AbstractSchematic depictions and original electron micrographs of cytoplasmic inclusions formed by native (tag-free) mutant Huntington exon1 proteins (Httex1 72Q, left) and the corresponding GFP fusion protein (Httex1 72Q-GFP).Competing Interest StatementThe authors have declared no competing interest. ER -