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Potential Effect of S-Nitrosylated Protein Disulfide Isomerase on Mutant SOD1 Aggregation and Neuronal Cell Death in Amyotrophic Lateral Sclerosis

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Abstract

Aggregation of misfolded protein and resultant intracellular inclusion body formation are common hallmarks of mutant superoxide dismutase (mSOD1)-linked familial amyotrophic lateral sclerosis (FALS) and have been associated with the selective neuronal death. Protein disulfide isomerase (PDI) represents a family of enzymatic chaperones that can fold nascent and aberrant proteins in the endoplasmic reticulum (ER) lumen. Recently, our group found that S-nitrosylated PDI could contribute to protein misfolding and subsequent neuronal cell death. However, the exact role of PDI in the pathogenesis of ALS remains unclear. In this study, we propose that PDI attenuates aggregation of mutant/misfolded SOD1 and resultant neurotoxicity associated with ER stress. ER stress resulting in PDI dysfunction therefore provides a mechanistic link between deficits in molecular chaperones, accumulation of misfolded proteins, and neuronal death in neurodegenerative diseases. In contrast, S-nitrosylation of PDI inhibits its activity, increases mSOD1 aggregation, and increases neuronal cell death. Specifically, our data show that S-nitrosylation abrogates PDI-mediated attenuation of neuronal cell death triggered by thapsigargin. Biotin switch assays demonstrate S-nitrosylated PDI both in the spinal cords of SOD1 (G93A) mice and human patients with sporadic ALS. Therefore, denitrosylation of PDI may have therapeutic implications. Taken together, our results suggest a novel strategy involving PDI as a therapy to prevent mSOD1 aggregation and neuronal degeneration. Moreover, the data demonstrate that inactivation of PDI by S-nitrosylation occurs in both mSOD1-linked and sporadic forms of ALS in humans as well as mice.

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010–0011008). Additional support came in part from NIH grants P01 HD29587, P01 ES016738, and P30 NS076411 (to SAL).

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Authors and Affiliations

  1. Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

    Gye Sun Jeon, Jeong-Seon Lee, Kwang-Woo Lee & Jung-Joon Sung

  2. Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, CA, 92037, USA

    Tomohiro Nakamura & Stuart A. Lipton

  3. Department of Neurology, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea

    Won-Jun Choi

  4. Department of Neurology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea

    Suk-Won Ahn

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  1. Gye Sun Jeon
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  2. Tomohiro Nakamura
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Correspondence to Jung-Joon Sung or Stuart A. Lipton.

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Jeon and Nakamura contributed equally to this work.

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Supplementary Fig. 1

mSOD1 is prone to aggregation and are largely insoluble in detergent. Note that PDI transfection decreased the quantity of mSOD1 protein in the detergent-insoluble fraction. Moc, mock transfection. (JPEG 16 kb)

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Supplementary Fig. 2

a, Flow cytometry determine the efficiency of transfection in NSC-34 cells with GFP and pcDNA empty vector, wild-type (WT) SOD1 or mSOD1 (G93A), plus wild-type PDI or mutant (MT) PDI. After 24 hours, cells were harvested and the numbers of GFP positive cells were estimated by flow cytometry. b, When CHX (10 μg/ml) was chased for the indicated period of time, PDI overexpression did not affect the stability of SOD1 protein. c, Wild-type PDI or mPDI did not affect SOD1 mRNA levels in the absence or presence of transfected wild-type SOD1 in NSC-34 cells. The data represent the mean of 3 independent experiments. (JPEG 38 kb)

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Supplementary Fig. 3

HEK293A cells transfected with mSOD1 compared to wild-type SOD1 manifest an equal degree of toxicity. PI-positive cells were examined to determine cell death. Cell death was not significantly different in mock-transfected (Moc), wild-type, or mSOD1 (G93A) cells, although there was a trend for transfected cells to manifest increased toxicity. (JPEG 24 kb)

High resolution image (TIFF 4338 kb)

Supplementary Fig. 4

NSC-34 cells transfected with mSOD1 compared to wild-type SOD1 manifest an increased degree of toxicity. PI-positive cells were examined to determine cell death. Cell death was significantly increased in mSOD1 (G93A) compared to mock-transfected (Moc) wild-type cells (values are mean + SEM, n = 3; *P < 0.01). (JPEG 21 kb)

High resolution image (TIFF 4196 kb)

Supplementary Fig. 5

Transfection of NSC-34 cells with mSOD1 (G93A) compared to WT SOD1 leads to a significant increase in cell death induced by 200 μM SNOC (values are mean + SEM, n = 3; *P < 0.01). (JPEG 28 kb)

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Supplementary Table 1

The information for human spinal cord samples. PMI: Postmortem interval (From time of death to freezing of the samples) (JPEG 13 kb)

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Jeon, G.S., Nakamura, T., Lee, JS. et al. Potential Effect of S-Nitrosylated Protein Disulfide Isomerase on Mutant SOD1 Aggregation and Neuronal Cell Death in Amyotrophic Lateral Sclerosis. Mol Neurobiol 49, 796–807 (2014). https://doi.org/10.1007/s12035-013-8562-z

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