S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.
Stress proteins located in the cytosol or endoplasmic reticulum (ER) maintain cell homeostasis and afford tolerance to severe insults. In neurodegenerative diseases, several chaperones ameliorate the accumulation of misfolded proteins triggered by oxidative or nitrosative stress, or of mutated gene products. Although severe ER stress can induce apoptosis, the ER withstands relatively mild insults through the expression of stress proteins or chaperones such as glucose-regulated protein (GRP) and protein-disulphide isomerase (PDI), which assist in the maturation and transport of unfolded secretory proteins. PDI catalyses thiol-disulphide exchange, thus facilitating disulphide bond formation and rearrangement reactions. PDI has two domains that function as independent active sites with homology to the small, redox-active protein thioredoxin. During neurodegenerative disorders and cerebral ischaemia, the accumulation of immature and denatured proteins results in ER dysfunction, but the upregulation of PDI represents an adaptive response to protect neuronal cells. Here we show, in brains manifesting sporadic Parkinson's or Alzheimer's disease, that PDI is S-nitrosylated, a reaction transferring a nitric oxide (NO) group to a critical cysteine thiol to affect protein function. NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leads to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. S-nitrosylation also abrogates PDI-mediated attenuation of neuronal cell death triggered by ER stress, misfolded proteins or proteasome inhibition. Thus, PDI prevents neurotoxicity associated with ER stress and protein misfolding, but NO blocks this protective effect in neurodegenerative disorders through the S-nitrosylation of PDI.
Uehara
Takashi
T
Center for Neuroscience and Aging, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Nakamura
Tomohiro
T
Yao
Dongdong
D
Shi
Zhong-Qing
ZQ
Gu
Zezong
Z
Ma
Yuliang
Y
Masliah
Eliezer
E
Nomura
Yasuyuki
Y
Lipton
Stuart A
SA
D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D019704:Protein Disulfide-Isomerases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
C480827:GPR37 receptor, human; D018832:Molecular Chaperones; D061988:Proteasome Inhibitors; D043562:Receptors, G-Protein-Coupled; D013438:Sulfhydryl Compounds; D025801:Ubiquitin; D009569:Nitric Oxide; D016202:N-Methylaspartate; D046988:Proteasome Endopeptidase Complex; D019704:Protein Disulfide-Isomerases; D003545:Cysteine