Transcriptome-guided modeling reveals insulin-related metabolic dysfunction in SCA3 mouse cerebellum.

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine neurodegenerative disorder in which metabolic involvement may extend beyond proteotoxicity alone. We integrated cerebellar RNA sequencing with transcriptome-constrained genome-scale metabolic modeling to characterize metabolic dysregulation in transgenic SCA3 (84Q) versus control (15Q) mice and to relate cerebellar changes to circulating insulin-related measures. Differential expression and preranked gene set enrichment analyses revealed coordinated suppression of insulin/glucose-homeostasis modules and lipid/sterol programs in the SCA3 cerebellum. Context-specific metabolic models derived from iMM1865 and analyzed using parsimonious flux balance analysis, flux variability analysis, and flux sampling indicated reduced oxidative metabolism together with increased nucleotide salvage, one-carbon metabolism, and proteostasis-associated remodeling. Distribution-level comparisons of sampled fluxes detected widespread network reorganization despite modest median shifts. Plasma insulin was elevated in 84Q mice, whereas cerebellar Ins2 and Igf1 transcripts were reduced, consistent with an insulin-related dysregulation signature. Together, these data support broad metabolic reprogramming in the SCA3 cerebellum, including insulin/IGF-related alterations, and nominate pathway-level candidates for future mechanistic validation.