Cardiorenal and hepatic dysfunctions underlie metabolic alterations in the spinocerebellar ataxia type 7 mice

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Abstract Spinocerebellar ataxia type 7 (SCA7) is a polyglutamine expansion disorder characterized by progressive cerebellar and retinal degeneration leading to ataxia and blindness. While mutant ATXN7 is ubiquitously expressed, most studies have focused on neurological symptoms, and peripheral contributions to pathology remain poorly understood. Here, we investigated systemic abnormalities in SCA7 140Q/5Q knock-in mice, a model of early-onset disease. Using longitudinal metabolic profiling, ultrasound imaging, and histopathology, we identified early and progressive dysfunction of the kidney, liver, and heart. Renal impairment was marked by uremia, polyuria with abnormal calcium and glucose excretion, tubular epithelial cell loss, and podocyte dedifferentiation, including the reappearance of primary cilia and pedicel effacement. Hepatic alterations included dysregulated lipid metabolism, elevated bilirubin, and reduced iron levels, contributing to anemia. Cardiac dysfunction manifested as reduced stroke volume as early as 11 weeks, suggesting a cardiorenal syndrome. Together, these organ-specific changes resulted in systemic metabolic disturbances such as dyslipidemia, iron deficiency anemia, thrombocytosis, and chronic inflammation, detectable before the onset of motor incoordination. Our findings demonstrate that peripheral organ dysfunction is an early and integral feature of SCA7 pathogenesis, with renal and cardiac impairments emerging prior to neurological decline. These results highlight the value of systemic biomarkers for disease monitoring and suggest that targeting peripheral pathology may provide therapeutic benefit. More broadly, they underscore the need to view SCA7 not solely as a neurodegenerative disorder but as a multi-organ disease.

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