High‐Fat Diet Exacerbates Neuropathology in a Transgenic Mouse Model of Multiple System Atrophy

BACKGROUND: Multiple system atrophy (MSA) is a rare and devastating neurodegenerative disorder. Accumulating clinical and preclinical evidence suggests that diabetes and insulin resistance may adversely influence MSA pathophysiology. OBJECTIVE: We investigated the potential association between diabetes, impaired glucose homeostasis, and MSA neuropathology in rodents. METHODS: We subjected the PLP-SYN (proteolipid promoter) transgenic mouse model of MSA to either a standard chow diet or a high-fat diet (HFD) for 4 months to induce diet-associated metabolic alterations. Metabolic, neuropathological, and behavioral parameters were subsequently evaluated at multiple time points. RESULTS: PLP-SYN mice fed a HFD exhibited a more pronounced diabetic phenotype, characterized by aggravated peripheral glucose dysregulation and insulin resistance, compared with wild-type mice on the same diet. Moreover, 4 months of HFD feeding aggravated MSA-related neuropathology, as evidenced by increased α-synuclein accumulation and enhanced dopaminergic neurodegeneration, accompanied by accelerated impairment of fine motor function. CONCLUSIONS: Collectively, these findings indicate an association between dysregulated glucose metabolism and MSA neuropathology. Our results further support the potential of modulating glucose metabolism to slow disease progression in MSA and provide additional rationale for exploring whether antidiabetic agents could provide therapeutic benefits. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.