Huntingtin and the presynapse. (A) Select examples demonstrating how wtHTT positively regulates endocytosis (left). Through associations with ADAM10 and piccolo, wtHTT regulates SV density at the readily releasable and reserve vesicle pools. Through associations with HIP1, AP-2 and ADAM10, wtHTT regulates clathrin-mediated endocytosis. wtHTT loss impairs endocytosis by disrupting the function of complexes with the aforementioned proteins (right). wtHTT LOF decreases SV density at the readily releasable and reserve vesicle pools and impairs clathrin-mediated endocytosis. (B) Select examples demonstrating how wtHTT positively regulates exocytosis. Through its associations with synapsin-1, HAP1 and HIP1, wtHTT can regulate the rate of SV exocytosis and the amount of neurotransmitter release. wtHTT loss disrupts exocytosis (right). (C) Select examples demonstrating how wtHTT positively regulates axonal transport (top). Through its associations with HAP1 and HIP1, as well as molecular motors, wtHTT maintains proper anterograde and retrograde transport of cellular cargoes including SVs and DCVs. wtHTT loss impairs axonal transport (bottom). Due to its associations with HAP1 and HIP1, as well as molecular motors, wtHTT loss interferes with anterograde and retrograde transport of cellular cargoes including SVs and DCVs. Abbreviations: LOF, loss of function; ADAM10, A disintegrin and metalloproteinase domain-containing protein 10; HIP1, huntingtin-interacting protein 1; AP-2, adaptor protein complex 2; SV, synaptic vesicle; HAP1, huntingtin-associated protein 1; DCV, dense-core vesicle. Figure created using Biorender.com.