2. Academic Validation
  3. DISC1 inhibits GSK3β activity to prevent tau hyperphosphorylation under diabetic encephalopathy

DISC1 inhibits GSK3β activity to prevent tau hyperphosphorylation under diabetic encephalopathy

  • Biofactors. 2022 Sep 7. doi: 10.1002/biof.1884.
Jiehui Chen 1,  Yong Liu 1,  Keru Zhou 2,  Wei Zhang 1 3,  Bin Wen 1 4,  Kai Xu 1 4,  Yazhou Liu 1 4,  Ling Chen 2,  Yue Huang 5,  Benhong He 5,  Weijian Hang 1 6,  Juan Chen 1 2 4
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2 Neonatal Intensive Care Unit, Department of Pediatric, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 School of Basic Medicine, Anhui Medical University, Hefei, Anhui, China.
  • 4 Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 5 Department of Cardiovascular Medicine, Lichuan People's Hospital, Lichuan, China.
  • 6 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
PMID: 36070513 DOI: 10.1002/biof.1884
Abstract

Diabetic encephalopathy (DE) is a common complication of type 2 diabetes (T2D), especially in those patients with long T2D history. Persistent high glucose (HG) stimulation leads to neuron damage and manifests like Alzheimer's disease's pathological features such as neurofilament tangle. However, the precise mechanism of high-glucose-induced tau hyperphosphorylation is not fully revealed. We here gave evidence that Disrupted in schizophrenia 1 protein (DISC1) could interact with glycogen synthase kinase 3β (GSK3β) and inhibit its activity to prevent tau hyperphosphorylation. By using DB/DB mice as animal model and HG-treated N2a cell as cell model, we found that DISC1 was downregulated both in vivo and in vitro, complicated with Tau hyperphosphorylation and GSK3β activation. Further, we identified DISC1 interacted with GSK3β by its 198th-237th amino acid residues. Overexpression of full length DISC1 but not mutated DISC1 lacking this domain could prevent HG induced tau hyperphosphorylation. Taken together, our work revealed DISC1 could be an important negative modulators of tau phosphorylation, and suggested that preservation of DISC1 could prevent HG induced neuron damage.

Keywords

DISC1; GSK3β; diabetic encephalopathy; tau hyperphosphorylation.

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