In conclusion, we have developed and characterized an AAV-based mouse model of SCA3 that exhibits ataxia-like defects in locomotor behavior, mutant ATXN3 and pTDP-43 inclusion pathology, cerebellar-specific neuronal degeneration, elevated CSF NFL levels, and increased plasma polyQ-ATXN3 levels. Here, NEFL is linked to cerebellar ataxia.