Central nervous system endoplasmic reticulum stress in a murine model of type 2 diabetes
- C. Sims-RobinsonAffiliated withDepartment of Neurology, University of Michigan
- , S. ZhaoAffiliated withDepartment of Neurology, University of MichiganDepartment of Electrical Engineering and Computer Science, University of Michigan
- , J. HurAffiliated withDepartment of Neurology, University of Michigan
- , E. L. FeldmanAffiliated withDepartment of Neurology, University of MichiganNational Center for Integrative Biomedical Informatics, University of Michigan Email author
Type 2 diabetes is associated with complications in the central nervous system (CNS), including learning and memory, and an increased risk for neurodegenerative diseases. The mechanism underlying this association is not understood. The aim of this study was to gain greater insight into the possible mechanisms of diabetes-induced cognitive decline.
We used microarray technology to identify and examine changes in gene expression in the hippocampus of a murine model of type 2 diabetes, the db/db mouse. Bioinformatics approaches were then used to investigate the biological significance of these genes. To validate the biological significance we evaluated mRNA and protein levels.
At 8 and 24 weeks, 256 and 822 genes, respectively, were differentially expressed in the db/db mice. The most significantly enriched biological functions were related to mitochondria, heat shock proteins, or the endoplasmic reticulum (ER), the majority of which were downregulated. The ER-enriched cluster was one of the clusters that contained the highest number of differentially expressed genes. Several of the downregulated genes that were differentially expressed at 24 but not at 8 weeks are directly involved in the unfolded protein response (UPR) pathway and include two heat shock proteins (encoded by Hspa5 and Hsp90b1), a transcriptional factor (x-box binding protein 1, encoded by Xbp1), and an apoptotic mediator (DNA-damage inducible transcript 3, encoded by Ddit3).
The changes that we observed in the UPR pathway due to ER stress may play a role in the pathogenesis of CNS complications in diabetes. The results of this study are a foundation for the development of pharmacological targets to reduce ER stress in diabetic hippocampi.
KeywordsBrain ER stress Gene expression Hippocampus Microarray Type 2 diabetes Unfolded protein response
- Central nervous system endoplasmic reticulum stress in a murine model of type 2 diabetes
Volume 55, Issue 8 , pp 2276-2284
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- ER stress
- Gene expression
- Type 2 diabetes
- Unfolded protein response
- Industry Sectors
- Author Affiliations
- 1. Department of Neurology, University of Michigan, 5017 AATBSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA
- 2. Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, USA
- 3. National Center for Integrative Biomedical Informatics, University of Michigan, Ann Arbor, MI, USA