Up-regulation of protein disulfide isomerase (PDI) is an adaptive response to accumulation of misfolded proteins in the endoplasmic reticulum (ER) that helps protect neurons from apoptosis resulting from ER stress. After determining that exposure to a nitric oxide (NO) donor or activation of neuronal NO synthase (nNOS) expressed in HEK-293T cells led to PDI S-nitrosylation, Uehara et al. showed that S-nitrosylated PDI was present in the brains of people who had had Parkinson's disease or Alzheimer's disease. S-nitrosylation impaired the ability of PDI to act as a chaperone (assayed by inhibition of guanidinium-dependent rhodanese aggregation) and an isomerase (assayed by renaturation of an inactive form of RNase A with scrambled disulfide bonds). When coexpressed with synphilin-1 in a dopaminergic neuroblastoma cell line, PDI inhibited the development of synphilin-1-dependent Lewy-body-like inclusions, a protective effect that was attenuated by NO. Exposure of cultured cortical neurons to N-methyl-D-aspartate (NMDA) led to NOS-sensitive accumulation of S-nitrosylated PDI, accumulation of polyubiquitinated proteins, and apoptosis; PDI overexpression decreased the number of polyubiquitinated and apoptotic cells and attenuated NMDA-dependent activation of the unfolded protein response. In neuroblastoma cells, PDI overexpression inhibited cell death in response to ER stress, inhibition of the proteasome, or overexpression of a protein that induces the unfolded protein response, protective effects that were reversed by exposure to a NO donor. Thus, the authors conclude that, in neurodegenerative disorders, S-nitrosylation of PDI by NO attenuates its ability to protect neurons from the neurotoxic effects of ER stress.
T. Uehara, T. Nakamura, D. Yao, Z.-Q. Shi, Z. Gu, Y. Ma, E. Masliah, Y. Nomura, S. A. Lipton, S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441, 513-517 (2006). [PubMed]