S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration

Takashi Uehara, Tomohiro Nakamura, Dongdong Yao, Zhong Qing Shi, Zezong Gu, Yuliang Ma, Eliezer Masliah, Yasuyuki Nomura, Stuart A. Lipton

Research output: Contribution to journalArticle

640 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)513-517
Number of pages5
JournalNature
Volume441
Issue number7092
DOIs
Publication statusPublished - May 25 2006
Externally publishedYes

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Protein Disulfide-Isomerases
Heat-Shock Proteins
Endoplasmic Reticulum Stress
Endoplasmic Reticulum
Neurodegenerative Diseases
Protein Unfolding
Nitric Oxide
Sulfhydryl Compounds
Disulfides
Proteins
Unfolded Protein Response
link protein
Thioredoxins
Proteasome Endopeptidase Complex
Brain Ischemia
Cytosol
Oxidation-Reduction
Cysteine
Parkinson Disease
Catalytic Domain

ASJC Scopus subject areas

  • General

Cite this

Uehara, T., Nakamura, T., Yao, D., Shi, Z. Q., Gu, Z., Ma, Y., ... Lipton, S. A. (2006). S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature, 441(7092), 513-517. https://doi.org/10.1038/nature04782

S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. / Uehara, Takashi; Nakamura, Tomohiro; Yao, Dongdong; Shi, Zhong Qing; Gu, Zezong; Ma, Yuliang; Masliah, Eliezer; Nomura, Yasuyuki; Lipton, Stuart A.

In: Nature, Vol. 441, No. 7092, 25.05.2006, p. 513-517.

Research output: Contribution to journalArticle

Uehara, T, Nakamura, T, Yao, D, Shi, ZQ, Gu, Z, Ma, Y, Masliah, E, Nomura, Y & Lipton, SA 2006, 'S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration', Nature, vol. 441, no. 7092, pp. 513-517. https://doi.org/10.1038/nature04782
Uehara, Takashi ; Nakamura, Tomohiro ; Yao, Dongdong ; Shi, Zhong Qing ; Gu, Zezong ; Ma, Yuliang ; Masliah, Eliezer ; Nomura, Yasuyuki ; Lipton, Stuart A. / S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. In: Nature. 2006 ; Vol. 441, No. 7092. pp. 513-517.
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