Multimodal characterization of sensorimotor peripheral neuropathy in a preclinical mouse model of SCA3

Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia caused by a toxic gain-of-function CAG expansion in ATXN3. Currently, no effective preventive or disease-modifying treatments exist for this uniformly fatal disorder. This progressive, multisystem disorder is typified by neuronal degeneration and demyelination of critical parts of the central nervous system. Additionally, more than half of individuals with SCA3 also exhibit peripheral neuropathy symptoms like reduced limb sensation or burning pains, significantly impacting quality of life and contributing to mobility impairments. However, exploration into cell types and disease mechanisms underlying the SCA3 peripheral nervous system abnormalities remains limited by lack of comprehensive SCA3 animal model characterizations. This study employs the transgenic full-length human mutant ATXN3 YACQ84 (Q84/Q84) mouse to assess progression of sensorimotor behaviors, nerve conduction abnormalities, and ultrastructural features of neuropathy. Nerve conduction studies in Q84/Q84 mice show prominent sensorimotor nerve conduction velocity reductions in the sciatic and sural nerves and blunted signal amplitudes in the sural nerve, suggestive of axon loss and demyelination. Behaviorally, Q84/Q84 mice display abnormal responses to thermal and mechanical stimuli. Histological analysis of Q84/Q84 peripheral nerves reveals combined neuronal and glial pathology, characterized by loss of both large myelinated and small unmyelinated fibers, alongside demyelination pathologies. Bulk analyses of Q84/Q84 dorsal root ganglia and sciatic nerves revealed sensory neuropathy-related transcriptional and splicing dysregulation spanning diverse somatosensory pathways. Our results characterize significant peripheral neuropathy in a representative SCA3 mouse model, providing a strong foundation for future mechanistic and therapeutic studies of peripheral neuropathy in SCA3.