Establishing Sensory Neurons as Therapeutic Targets in Peripheral Neuropathy Driven by Polyglutamine Expanded ATXN3

Objective Repeat expansion mutations underlie diverse neurogenetic disorders, many involving the peripheral nervous system. Despite peripheral neuropathy being the most common neurological disorder worldwide, its contribution to repeat expansion diseases remains poorly defined, and robust preclinical models are limited. We established a translational framework to study peripheral neuropathy in Spinocerebellar ataxia type 3 (SCA3), a fatal multisystem disorder caused by a pathogenic CAG expansion in ATXN3. Methods SCA3 Knock-In Atxn3Q300/Q6 (KI) and Atxn3-/- Knock-Out (KO) mice underwent sensorimotor nerve conduction and behavioral testing. Peripheral tissues were evaluated for SCA3-related pathology, and transcriptional changes in KI dorsal root ganglia (DRG) were assessed by bulk RNA sequencing. To test therapeutic relevance, we generated a conditional “OFF” SCA3 knock-in (cKI) mouse and crossed it with Avil-Cre to selectively silence mutant ATXN3 in sensory neurons. Peripheral phenotyping was repeated in Avil-Cre; cKI mice. Results KI mice developed progressive sensorimotor deficits, peripheral histopathology, and RNA splicing dysregulation that parallel clinical features of SCA3. In contrast, KO mice showed normal peripheral nerve function, implicating toxic gain-of-function from mutant ATXN3 as the causative driver. Sensory neuron–specific silencing of mutant ATXN3 significantly ameliorated peripheral nerve abnormalities. Interpretation These findings define a pathogenic role for repeat expansion–driven peripheral nerve degeneration in SCA3, identify sensory neurons as key therapeutic targets, and provide a preclinical platform for developing peripheral interventions in SCA3 and related repeat expansion disorders.