BMI Progress Reports 2021 // Prof. Lashuel's Lab, N. Riguet "Mechanisms of inclusion formation in Huntington’s disease: Lessons from cellular models"
Huntington’s Disease (HD) is a genetic, progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric symptoms. 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 are not yet fully understood. This knowledge is crucial for developing reliable preclinical models and to develop effective therapies and disease modifying strategies.
Towards addressing this knowledge gap, we investigated the mechanisms of Htt aggregation and inclusion formation in cellular models of HD. We applied correlative light- and electron microscopy (CLEM) and quantitative proteomics to investigate the ultrastructural properties and protein composition of cytoplasmic and nuclear Htt aggregates (inclusions) formed in both mammalian cells and neurons. Our findings provide novel insight into the ultrastructural properties of cytoplasmic and nuclear Httex1 inclusions and their mechanisms of formation. We show that Httex1 inclusion formation and maturation are complex multi-stage processes that are driven and modulated by specific sequences of the exon1 and involve the sequestration of lipids, cytoplasmic and cytoskeletal proteins related to HD dysregulated pathways. We also show that formation of Httex1 inclusions formation lead to the accumulation of remodeled or dysfunctional membranous organelles and the impairment of the protein quality control and degradation machineries. Interestingly, nuclear and cytoplasmic Httex1 inclusions exhibited distinct biochemical composition and ultrastructural properties, suggesting that the cellular environment is an important determinant of Htt aggregation and toxicity. These findings and their implication for the understanding of the pathogenesis of HD and developing novel therapeutic approaches for treating HD will be discussed.