Huntingtin polyglutamine expansions misdirect axonal transport by perturbing motor and adaptor recruitment.

Huntington's disease is caused by polyglutamine (polyQ) expansions in huntingtin (HTT). PolyQ lengths >35Q lead to neurodegeneration, and longer repeats correspond to earlier onset of symptoms. HTT scaffolds kinesin-1 and dynein to organelles directly and through adaptors. We tracked BDNF vesicles, mitochondria, and lysosomes in stem-cell-derived neurons engineered to express HTT with polyQ lengths of 30, 45, 65, and 81. BDNF endosomes were more motile in HTT-45Q and HTT-65Q neurons and misdirected toward the distal tip in HTT-81Q neurons. Under neuroinflammatory stress, polyQ expansions resulted in fewer BDNF cargoes and more lysosomes. We next isolated BDNF endosomes from neurons and counted the associated motors and adaptors. We found BDNF endosomes associated with greater numbers of kinesin-1 and HAP1 molecules in HTT-81Q neurons. Together, these results show that polyQ expansions in HTT alter the motors and adaptors recruited to cargoes, resulting in dysregulated transport and responses to neuroinflammatory stress.