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Development of Recombinant Proteins to Treat Chronic Pain
Published on: April 11, 2018
Translational control by general control nonderepressible 2 kinase regulates methylglyoxal-induced pain in mice
Angela R Meyer1, Guadalupe García1, Alexander R Mikesell1
1Department of Anesthesiology, University of Wisconsin-Madison, Madison, WI, United States.
Abstract:
Neuropathic pain is pervasive among people with diabetes. The integrated stress response (ISR) is a key mechanism of translational regulation implicated in diabetic pain. In this study, we demonstrate that a reactive glycolytic metabolite, methylglyoxal (MGO), which is strongly associated with painful diabetic neuropathy, activates the ISR through the kinase general control nonderepressible 2 (GCN2). Methylglyoxal disrupts elongating ribosomes, triggering the recruitment of ribosome quality control factors and collision sensors. GCN2 activation by MGO requires the ribosomal P-stalk, a critical sensor for elongation factors. Moreover, neuronal sensitization and mechanical allodynia produced by MGO are GCN2-dependent. Overall, this study links ribosomal elongation dysfunction to metabolic pain and identifies GCN2 as a novel analgesic target for diabetic neuropathy.
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