Huntingtin and its allies at the cortico-striatal synapse

Abstract Huntington’s Disease (HD) is characterized by progressive motor and cognitive decline, largely driven by cortico-striatal synaptic dysfunction. Central to these processes is huntingtin (HTT) protein, which is abundantly present at the synapse. HTT regulates the synaptic vesicle cycle at presynaptic terminals and serves as a scaffold at the postsynaptic density where it modulates receptor dynamics. An expanding network of HTT-interacting proteins (HIPs), crucial for maintaining synaptic structure and function, underscores the role of HTT as a core component of synaptic integrity. This review examines the 30-year research journey that has unveiled HTT pre- and postsynaptic partners, with focus on experimentally validated interactors and their involvement in HD cortico-striatal synaptic dysfunction.