Investigating Peripheral Neuropathy in Spinocerebellar Ataxia Type 3

ABSTRACT Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia and currently has no effective treatment. This progressive, multisystem disorder is typified by the degeneration of critical parts of the central nervous system including the cerebellum, brainstem, basal ganglia, and spinal cord. Moreover, neuropathological studies show widespread involvement of the peripheral nervous system (PNS). Despite the focus of past research on the central nervous system, peripheral neuropathy symptoms are prominently observed in over half of SCA3 patients. This research aims to deeply understand SCA3 disease, particularly exploring its impact on the PNS and its connection to peripheral neuropathy. Our preliminary data in two SCA3 mouse models confirm that both exhibit peripheral neuropathy that mirrors human features. Postmortem tissue analysis and preliminary SCA3 mouse studies point towards the dysregulation of selective subtypes of dorsal root ganglion sensory neurons and demyelination as potential instigators of peripheral neuropathy onset in SCA3 patients. This research employs SCA3 mouse models to analyze peripheral neuropathy onset and progression through functional, histological, and transcriptional studies. Ultimately, our research aims to illuminate a cell-type specific mechanistic understanding of SCA3 peripheral neuropathy, paving the way for potential therapeutic interventions in this crucial area that might have implications for other multisystem neurodegenerative disorders.