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  3. Dual-specificity tyrosine phosphorylation-regulated kinase 1A ameliorates insulin resistance in neurons by up-regulating IRS-1 expression

Dual-specificity tyrosine phosphorylation-regulated kinase 1A ameliorates insulin resistance in neurons by up-regulating IRS-1 expression

  • J Biol Chem. 2019 Dec 27;294(52):20164-20176. doi: 10.1074/jbc.RA119.010809.
Shijiao Tian 1 2,  Wenming Jia 3,  Mei Lu 4,  Juan Zhao 3,  Xiulian Sun 5 6
Affiliations

Affiliations

  • 1 Department of Neurology, Qilu Hospital of Shandong University, No. 107 Wenhuaxi Rd., 250012 Jinan, China.
  • 2 Brain Research Institute, Qilu Hospital of Shandong University, No. 107 Wenhuaxi Rd., 250012 Jinan, China.
  • 3 NHC Key Laboratory of Otorhinolaryngology, Chinese Ministry of Health, Qilu Hospital of Shandong University, No. 44 Wenhuaxi Rd., 250012 Jinan, China.
  • 4 Department of Geriatrics, Qilu Hospital of Shandong University, No. 107 Wenhuaxi Rd., 250012 Jinan, China.
  • 5 Brain Research Institute, Qilu Hospital of Shandong University, No. 107 Wenhuaxi Rd., 250012 Jinan, China xiulians@gmail.com.
  • 6 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission, Qilu Hospital of Shandong University, No. 107 West Wenhua Rd., Jinan, 250012 Shandong Province, China.
PMID: 31723029 DOI: 10.1074/jbc.RA119.010809
Abstract

Insulin resistance in the brain is a pathological mechanism that is shared between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Although aberrant expression and phosphorylation of Insulin Receptor substrate 1 (IRS-1) contribute to Insulin resistance, the underlying mechanism remains elusive. In this study, we used several approaches, including adeno-associated virus-based protein overexpression, immunoblotting, immunoprecipitation, immunohistochemistry, and in situ proximal ligation assays, to investigate the function of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in IRS-1 regulation and the downstream Insulin signaling in neurons. We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing turnover of the IRS-1 protein. We further observed that DYRK1A directly interacted with IRS-1 and phosphorylated IRS-1's multiple serine residues. Of note, DYRK1A and IRS-1 were coordinately up-regulated in the prefrontal cortex of db/db mice brain. Furthermore, DYRK1A overexpression ameliorated chronic high insulin-induced Insulin resistance in SH-SY5Y cells as well as in primary rat neurons. These findings suggest that DYRK1A protects against Insulin resistance in the brain by elevating IRS-1 expression.

Keywords

Alzheimer disease; DYRK1A; brain neuron; db/db mouse; diabetes; insulin receptor substrate 1 (IRS-1); insulin resistance; metabolic disorder; neurodegenerative disease.

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