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.
Abstract
Journal Article
eng
42386068
Pan, Shin-Hung, et al. "Transcriptome-guided Modeling Reveals Insulin-related Metabolic Dysfunction in SCA3 Mouse Cerebellum." Brain Research, 2026, p. 150451.
Pan SH, Chang JC, Cheng WL, et al. Transcriptome-guided modeling reveals insulin-related metabolic dysfunction in SCA3 mouse cerebellum. Brain Res. 2026.
Pan, S. H., Chang, J. C., Cheng, W. L., Wei, A. C., & Liu, C. S. (2026). Transcriptome-guided modeling reveals insulin-related metabolic dysfunction in SCA3 mouse cerebellum. Brain Research, 150451. https://doi.org/10.1016/j.brainres.2026.150451
Pan SH, et al. Transcriptome-guided Modeling Reveals Insulin-related Metabolic Dysfunction in SCA3 Mouse Cerebellum. Brain Res. 2026 Jul 1;150451. PubMed PMID: 42386068.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR
T1 - Transcriptome-guided modeling reveals insulin-related metabolic dysfunction in SCA3 mouse cerebellum.
AU - Pan,Shin-Hung,
AU - Chang,Jui-Chih,
AU - Cheng,Wen-Ling,
AU - Wei,An-Chi,
AU - Liu,Chin-San,
Y1 - 2026/07/01/
PY - 2026/5/22/received
PY - 2026/6/26/revised
PY - 2026/6/30/accepted
PY - 2026/7/2/medline
PY - 2026/7/2/pubmed
PY - 2026/7/1/entrez
KW - Cerebellum
KW - Genome-scale metabolic modeling
KW - Insulin/IGF signaling
KW - Metabolic reprogramming
KW - Spinocerebellar ataxia type 3
KW - Transcriptomics
SP - 150451
EP - 150451
JF - Brain research
JO - Brain Res
N2 - 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.
SN - 1872-6240
UR - https://www.unboundmedicine.com/prime/citation/42386068/Transcriptome-guided_modeling_reveals_insulin-related_metabolic_dysfunction_in_SCA3_mouse_cerebellum.
DB - PRIME
DP - Unbound Medicine
ER -
