Role of Endoplasmic Reticulum Stress in Diabetic Neuropathy

  1. Norman E. Cameron
  1. From the School of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, U.K
  1. Corresponding author: Norman E. Cameron, n.e.cameron{at}

Neuropathy affects up to 50% of people with diabetes and is a major risk factor for foot ulceration and amputation (1). The etiology is multifactorial, and currently there is no satisfactory treatment except maintenance of good glycemic control (2), thereby highlighting the importance of identifying novel therapeutic targets.

The endoplasmic reticulum (ER) forms a membranous network throughout the cytosol and is contiguous with the outer nuclear membrane. The ER has three major functions: 1) synthesis, folding, and maturation of proteins; 2) Ca2+ storage; and 3) lipid biosynthesis. The ER provides a Ca2+-rich oxidizing environment for the formation of disulphide bonds and accurate protein folding. This process is controlled by Ca2+-dependent molecular chaperones and protein-folding enzymes such as glucose-regulated protein 78/immunoglobulin binding protein (GRP78/BiP), glucose-regulated protein 94, and protein disulfide isomerase. Folding to produce the native protein conformation is a complex, energy-requiring process. This process may be disrupted in pathological conditions, resulting in a buildup of misfolded and potentially toxic proteins that give rise to ER stress. Homeostatic responses to ER stress comprise the unfolded protein response (UPR). The UPR consists of signaling systems (Fig. 1) that are based on three transmembrane stress sensors. 1) The first is PKR-like eukaryotic initiation factor 2A kinase (PERK). Normally, PERK is bound to the chaperone GRP78/BiP, but as unfolded proteins accumulate GRP78/BiP dissociates, thereby activating PERK, which then phosphorylates eukaryotic initiation factor 2α, ultimately leading to general inhibition of protein translation and synthesis. 2) GRP78/BiP also dissociates from inositol-requiring enzyme 1, which mediates mRNA …

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