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Research ArticleResearch Article: New Research, Disorders of the Nervous System

The SUMO Conjugase Ubc9 Protects Dopaminergic Cells from Cytotoxicity and Enhances the Stability of α-Synuclein in Parkinson’s Disease Models

Dinesh Kumar Verma, Anurupa Ghosh, Lindsey Ruggiero, Etienne Cartier, Eric Janezic, Dionne Williams, Eui-Gil Jung, Michael Moore, Jong Bok Seo and Yong-Hwan Kim
eNeuro 4 September 2020, 7 (5) ENEURO.0134-20.2020; DOI: https://doi.org/10.1523/ENEURO.0134-20.2020
Dinesh Kumar Verma
1Department of Biological Sciences/Neuroscience program, Delaware State University, Dover, DE 19901
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Anurupa Ghosh
1Department of Biological Sciences/Neuroscience program, Delaware State University, Dover, DE 19901
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Lindsey Ruggiero
1Department of Biological Sciences/Neuroscience program, Delaware State University, Dover, DE 19901
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Etienne Cartier
1Department of Biological Sciences/Neuroscience program, Delaware State University, Dover, DE 19901
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Eric Janezic
1Department of Biological Sciences/Neuroscience program, Delaware State University, Dover, DE 19901
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Dionne Williams
1Department of Biological Sciences/Neuroscience program, Delaware State University, Dover, DE 19901
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Eui-Gil Jung
3Seoul Center, Korea Basic Science Institute, Seoul 02841, Republic of Korea
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Michael Moore
2Imaging Core, Delaware State University, Dover, DE 19901
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Jong Bok Seo
3Seoul Center, Korea Basic Science Institute, Seoul 02841, Republic of Korea
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Yong-Hwan Kim
1Department of Biological Sciences/Neuroscience program, Delaware State University, Dover, DE 19901
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Abstract

Small ubiquitin-like modifier (SUMO) is a widespread regulatory mechanism of post-translational modification (PTM) that induces rapid and reversible changes in protein function and stability. Using SUMO conjugase Ubc9-overexpressing or knock-down cells in Parkinson’s disease (PD) models, we demonstrate that SUMOylation protects dopaminergic cells against MPP+ or preformed fibrils (PFFs) of α-synuclein (α-syn)-induced toxicities in cell viability and cytotoxicity assays. In the mechanism of protection, Ubc9 overexpression significantly suppressed the MPP+ or PFF-induced reactive oxygen species (ROS) generation, while Ubc9-RNAi enhanced the toxicity-induced ROS production. Further, PFF-mediated protein aggregation was exacerbated by Ubc9-RNAi in thioflavin T staining, compared with NC1 controls. In cycloheximide (Chx)-based protein stability assays, higher protein level of α-syn was identified in Ubc9-enhanced green fluorescent protein (EGFP) than in EGFP cells. Since there was no difference in endogenous mRNA levels of α-syn between Ubc9 and EGFP cells in quantitative real-time PCR (qRT-PCR), we assessed the mechanisms of SUMO-mediated delayed α-syn degradation via MG132, proteasomal inhibitor, and PMA, lysosomal degradation inducer. Ubc9-mediated SUMOylated α-syn avoided PMA-induced lysosomal degradation because of its high solubility. Our results suggest that Ubc9 enhances the levels of SUMO1 and ubiquitin on α-syn and interrupts SUMO1 removal from α-syn. In immunohistochemistry, dopaminergic axon tips in the striatum and cell bodies in the substantia nigra from Ubc9-overexpressing transgenic mice were protected from MPTP toxicities compared with wild-type (WT) siblings. Our results support that SUMOylation can be a regulatory target to protect dopaminergic neurons from oxidative stress and protein aggregation, with the implication that high levels of SUMOylation in dopaminergic neurons can prevent the pathologic progression of PD.

  • α-synuclein
  • degradation
  • lysosome
  • proteostasis
  • SUMOylation
  • Ubc9

Footnotes

  • The authors declare no competing financial interests.

  • This work was supported by the National Institutes of Health Grant 5P20GM103653 (to Y.-H.K.).

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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eneuro: 7 (5)
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The SUMO Conjugase Ubc9 Protects Dopaminergic Cells from Cytotoxicity and Enhances the Stability of α-Synuclein in Parkinson’s Disease Models
Dinesh Kumar Verma, Anurupa Ghosh, Lindsey Ruggiero, Etienne Cartier, Eric Janezic, Dionne Williams, Eui-Gil Jung, Michael Moore, Jong Bok Seo, Yong-Hwan Kim
eNeuro 4 September 2020, 7 (5) ENEURO.0134-20.2020; DOI: 10.1523/ENEURO.0134-20.2020

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The SUMO Conjugase Ubc9 Protects Dopaminergic Cells from Cytotoxicity and Enhances the Stability of α-Synuclein in Parkinson’s Disease Models
Dinesh Kumar Verma, Anurupa Ghosh, Lindsey Ruggiero, Etienne Cartier, Eric Janezic, Dionne Williams, Eui-Gil Jung, Michael Moore, Jong Bok Seo, Yong-Hwan Kim
eNeuro 4 September 2020, 7 (5) ENEURO.0134-20.2020; DOI: 10.1523/ENEURO.0134-20.2020
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Keywords

  • α-synuclein
  • degradation
  • lysosome
  • proteostasis
  • SUMOylation
  • Ubc9

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