Redox Dyshomeostasis Links Renal and Neuronal Dysfunction in Drosophila Models of Gaucher and Parkinson's Disease

Abstract

Gaucher disease (GD), the most common lysosomal storage disorder, is caused by bi-allelic mutations in the GBA1 gene. Variants in GBA1 also represent the most frequent genetic risk factor for Parkinsons disease (PD). Although GD and PD are clinically distinct disorders, they share key pathological features, including lysosomal dysfunction, mitochondrial stress, and redox imbalance. While PD has traditionally been studied in the context of neuronal decline, the contribution of non-neuronal organ systems remains poorly understood. Here, we demonstrate that progressive renal dysfunction is a central, disease-modifying feature in Drosophila models of GD and PD. We show that Drosophila lacking either the main fly orthologue of GBA1, Gba1b, or the mitophagy regulator Parkin, exhibit age-dependent degeneration of the renal system. This includes disorganisation of the Malpighian tubules, impaired nephrocyte function, redox imbalance, and lipid accumulation. These renal defects contribute to systemic physiological decline, including water retention, ionic hypersensitivity, and exacerbation of neurodegenerative phenotypes. Importantly, we identify redox dyshomeostasis, rather than classical oxidative stress, as a central pathogenic driver, marked by paradoxical sensitivity to both oxidative and reductive interventions. Notably, treatment with the mTOR inhibitor rapamycin selectively restores renal structure and function in Gba1b mutants, but not in Parkin mutants, revealing mechanistic divergence between lysosomal and mitochondrial stress. These findings uncover redox imbalance as a biomarker of renal vulnerability and establish the renal system as a critical, potentially disease-modifying organ in the systemic progression of GD and PD.