A026 Lipids in focus: a promising path to Huntington disease therapy

<h3></h3> The CAG-repeat sequence, responsible for Huntington disease (HD), encodes a polyglutamine (polyQ) track in the protein which mediates its aggregation into intracellular inclusions. This event ends up in neurodegeneration and leads to changes in mood, cognition, and movement. However, recent work from our lab, alongside emerging evidence, reveals that there is also an alteration in lipid levels. Given the established link between lipids and other central nervous system disorders, we evaluated the impact of lipid metabolism in in vivo HD models by inducing or impairing lipid synthesis via different approaches. We measured polyQ-toxicity-related parameters, such as the number of polyQ-containing aggregates, thrashing rate, and touch response, in C. elegans deficient for oleic acid (OA) synthesis. The worms showed higher aggregation and decreased thrashing and touch response, with normal values being restored after exogenous administration of OA. Conversely, overexpressing a fatty acid synthase resulted in a strong rescue of polyQ-toxicity, suggesting that promoting lipogenesis is beneficial for HD. Moreover, treatment with a compound that has been suggested to enhance lipogenesis, rosiglitazone, either alone or combined, improved the health-state of the worms. Lipidomic analyses were performed to further confirm changes in composition or quantity between conditions. Our findings indicate that lipid metabolism plays a critical role in modulating the disease pathogenesis. Deficiencies in OA synthesis exacerbate polyQ toxicity, while overexpression of a fatty acid synthase and treatments aimed at enhancing lipogenesis significantly improve it. Our work highlights the promising value of molecules that modulate lipid synthesis as druggable targets to treat HD.