Accumulation of misfolded protein through nitrosative stress linked to neurodegenerative disorders.
Protein quality control is a critical feature of intracellular homeostasis. In particular, unfolded or misfolded proteins resulting from environmental stresses or free radicals are rapidly degraded via the ubiquitin-proteasome pathway. Nitric oxide (NO), a free radical gas, has been reported to be involved in such processes as vasorelaxation and neurotransmission. Conversely, NO also is implicated in neuronal cell death or neurodegeneration. Recent reports suggest that S-nitrosylation of proteins is a significant cause of neural dysfunction leading to neurodegenerative disorders. Specifically, S-nitrosylation of parkin eventually leads to the accumulation of unfolded proteins and subsequent neuronal death. The focus of this review is the identity of the target of NO. Nitrosative stress prevents normal functioning of the endoplasmic reticulum (ER) via S-nitrosylation of protein-disulfide isomerase (PDI), which is located in the ER lumen. This may contribute to the accumulation of misfolded proteins, as well as sustained activation of the unfolded protein response (UPR) pathway. These phenomena may be linked to the development of sporadic neurodegenerative diseases.
Uehara
Takashi
T
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. uehara@pharm.hokudai.ac.jp
D000818:Animals; D016923:Cell Death; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D018384:Oxidative Stress; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D017510:Protein Folding; D015398:Signal Transduction
D009569:Nitric Oxide; D019704:Protein Disulfide-Isomerases