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

Area of Science:

• Neuroscience
• Metabolic Engineering
• Genomics

Background:

• Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine neurodegenerative disorder.
• Metabolic dysregulation may contribute to SCA3 pathogenesis beyond proteotoxicity.

Purpose of the Study:

• To characterize metabolic dysregulation in the SCA3 cerebellum.
• To link cerebellar metabolic changes to circulating insulin-related measures.

Main Methods:

• Integrated cerebellar RNA sequencing with transcriptome-constrained genome-scale metabolic modeling.
• Utilized parsimonious flux balance analysis, flux variability analysis, and flux sampling on context-specific metabolic models.
• Compared transcriptomic and metabolic flux data between transgenic SCA3 (84Q) and control (15Q) mice.

Main Results:

• Identified coordinated suppression of insulin/glucose homeostasis and lipid/sterol programs in the SCA3 cerebellum.
• Metabolic modeling revealed reduced oxidative metabolism, increased nucleotide salvage, one-carbon metabolism, and proteostasis remodeling.
• Observed widespread metabolic network reorganization and an insulin-related dysregulation signature (elevated plasma insulin, reduced cerebellar Ins2 and Igf1 transcripts).

Conclusions:

• SCA3 involves broad metabolic reprogramming in the cerebellum, extending beyond proteotoxicity.
• Insulin/IGF-related alterations are implicated in SCA3 pathogenesis.
• Identified specific metabolic pathways as potential targets for future mechanistic studies and therapeutic development.