HUNTINGTIN FUNCTIONS AS A SCAFFOLDING PROTEIN IN GROWTH CONES TO REGULATE CYTOSKELETON ORGANIZATION AND AXONAL GROWTH

Huntingtin (HTT) is a multifunctional scaffolding protein involved in diverse cellular processes, including vesicular transport along the microtubule network, cell division, endocytosis, transcription, and RNA splicing. Expansion of the polyglutamine tract in the first exon of the HTT gene causes Huntington’s disease, a neurodegenerative disorder with strong links to abnormal cortical neurodevelopment. While HTT is well known for its microtubule-related functions, a recent study has revealed that it also associates with the actin cytoskeleton in axonal growth cones, where it contributes to the organization of F-actin bundles. To further elucidate the role of HTT in actin cytoskeleton organization, we identified proteins associated to F-actin specifically in the presence of HTT. Among these, we focused on proteins present in axonal growth cones with established roles in neurodevelopment. Our analyses revealed a complex spatial organization of HTT and these interacting proteins within growth cones in relation to the actin cytoskeleton. Notably, depletion of HTT disrupted the organization of its interaction partners, leading to altered cytoskeleton architecture and impaired axonal growth. Together, these findings uncover a novel role for HTT as a scaffolding protein regulating actin dynamics in axonal growth cones and provide new insights into neurodevelopmental mechanisms that may contribute to the pathogenesis of Huntington’s disease.