Beyond the brain: Polyglutamine disease pathology outside the nervous system.

Polyglutamine diseases are primarily age-dependent neurodegenerative disorders, but patient-based data also point to a broader, multisystem biology. Clinical, imaging, biochemical, and post-mortem studies support peripheral involvement across multiple organ systems in the onset and progression of Huntington's Disease, Spinal and Bulbar Muscular Atrophy, Dentatorubral-Pallidoluysian Atrophy, and six Spinocerebellar Ataxias. Various peripheral abnormalities often emerge before or alongside overt neurological symptoms, contribute to disability and mortality, and are only partly explained by deconditioning or medications. Current data support viewing polyglutamine diseases as systemic protein-misfolding syndromes with organ-selective vulnerability, where peripheral tissues both mirror and modify CNS pathology in humans. Here, we propose that integrated, longitudinal, multisystem phenotyping and targeted organ-directed interventions are essential components of future research investigations, clinical care, and trial design.