Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity

Huntington disease (HD) is caused by expansion of a glutamine repeat in the amino-terminal region of huntingtin. Despite its widespread expression, mu tant huntingtin induces selective neuronal loss in striatal neurons. Here w e report that, in mutant mice expressing HD repeats, the production and agg regation of N-terminal huntingtin fragments preferentially occur in HD-affe cted neurons and their processes and axonal terminals. N-terminal fragments of mutant huntingtin form aggregates and induce neuritic degeneration in c ultured striatal neurons. N-terminal mutant huntingtin also binds to synapt ic vesicles and inhibits their glutamate uptake in vitro. The specific proc essing and accumulation of toxic fragments of N-terminal huntingtin in HD-a ffected striatal neurons, especially in their neuronal processes and axonal terminals, may contribute to the selective neuropathology of HD.