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Age-Associated Insolubility of Parkin in Human Midbrain is Linked to Redox Balance and Sequestration of Reactive Dopamine Metabolites

Jacqueline M. Tokarew, View ORCID ProfileDaniel N. El-Kodsi, Nathalie A. Lengacher, Travis K. Fehr, Angela P. Nguyen, Bojan Shutinoski, Brian O’Nuallain, Ming Jin, Jasmine M. Khan, Andy C. H. Ng, Juan Li, Qiubo Jiang, Mei Zhang, Liqun Wang, Rajib Sengupta, Kathryn R. Barber, An Tran, Stephanie Zandee, View ORCID ProfileXiajun Dong, Clemens R. Scherzer, Alexandre Prat, Eve Tsai, Masashi Takanashi, Nobutaka Hattori, Jennifer A. Chan, Luigi Zecca, View ORCID ProfileAndrew B. West, Arne Holmgren, Lawrence Puente, Gary S. Shaw, Gergely Toth, John M. Woulfe, Peggy Taylor, View ORCID ProfileJulianna J. Tomlinson, Michael G. Schlossmacher
doi: https://doi.org/10.1101/2020.11.20.392175
Jacqueline M. Tokarew
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
2Graduate Program in Cellular and Molecular Medicine (Neuroscience), Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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Daniel N. El-Kodsi
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
2Graduate Program in Cellular and Molecular Medicine (Neuroscience), Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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  • ORCID record for Daniel N. El-Kodsi
Nathalie A. Lengacher
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
2Graduate Program in Cellular and Molecular Medicine (Neuroscience), Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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Travis K. Fehr
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
2Graduate Program in Cellular and Molecular Medicine (Neuroscience), Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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Angela P. Nguyen
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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Bojan Shutinoski
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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Brian O’Nuallain
3BioLegend Inc., Dedham, MA., USA
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Ming Jin
3BioLegend Inc., Dedham, MA., USA
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Jasmine M. Khan
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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Andy C. H. Ng
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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Juan Li
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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Qiubo Jiang
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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Mei Zhang
4Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, Canada
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Liqun Wang
3BioLegend Inc., Dedham, MA., USA
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Rajib Sengupta
5Department of Biochemistry, Karolinska Institute, Stockholm, Sweden
5*Present Address: Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal 700135, India
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Kathryn R. Barber
6Department of Biochemistry, University of Western Ontario, London, ON, Canada
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An Tran
6Department of Biochemistry, University of Western Ontario, London, ON, Canada
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Stephanie Zandee
7Department of Neuroscience, Faculty of Medicine, University of Montreal, Montreal, QC, Canada
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Xiajun Dong
8Ann Romney Center for Neurologic Diseases, Brigham & Women’s Hospital, Boston, MA, USA
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Clemens R. Scherzer
8Ann Romney Center for Neurologic Diseases, Brigham & Women’s Hospital, Boston, MA, USA
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Alexandre Prat
7Department of Neuroscience, Faculty of Medicine, University of Montreal, Montreal, QC, Canada
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Eve Tsai
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
9Division of Neurosurgery, Department of Surgery, The Ottawa Hospital, Ottawa, ON, Canada
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Masashi Takanashi
10Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
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Nobutaka Hattori
10Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
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Jennifer A. Chan
11Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, AB, Canada
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Luigi Zecca
12Institute of Biomedical Technologies, Italian National Research Council, Segrate (Milano), Italy
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Andrew B. West
13Departments of Neurobiology and Pharmacology & Cancer Biology, Duke University, Durham, NC, USA
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Arne Holmgren
5Department of Biochemistry, Karolinska Institute, Stockholm, Sweden
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Lawrence Puente
14Proteomics Core Facility, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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Gary S. Shaw
6Department of Biochemistry, University of Western Ontario, London, ON, Canada
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Gergely Toth
15Institute of Organic Chemistry, Research Center for Natural Sciences, Budapest, Hungary
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John M. Woulfe
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
4Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, Canada
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Peggy Taylor
3BioLegend Inc., Dedham, MA., USA
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Julianna J. Tomlinson
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
16University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
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Michael G. Schlossmacher
1Program in Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada
16University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
17Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
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  • For correspondence: mschlossmacher@ohri.ca
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Abstract

The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions, which are reflected in its posttranslational modifications. We found that in human control brain, including the S. nigra, parkin is largely insoluble after age 40 years, which is linked to its oxidation, e.g., at Cys95 and Cys253. In mice, oxidative stress increases posttranslational modifications at parkin cysteines and reduces its solubility. Oxidation of recombinant parkin also promotes insolubility and aggregate formation, but in parallel, lowers hydrogen peroxide (H2O2). This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. Intriguingly, in parkin-deficient human brain H2O2 concentrations are elevated. In prkn-null mice, H2O2 levels are dysregulated under oxidative stress conditions, such as acutely by MPTP-toxin exposure or chronically due to a second genetic hit. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic M17 cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at primate-specific Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation. In sections of normal, adult human midbrain, parkin specifically co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these redox effects may augment oxidative stress in dopamine producing neurons of mutant PRKN allele carriers, thereby contributing to neurodegeneration.

Competing Interest Statement

Drs. B. ONuallain, M. Jin, L. Wang, P. Taylor are (or were) employees of BioLegend Inc. (Dedham, MA., USA). The Ottawa Hospital receives payments from BioLegend Inc. related to licensing agreements for immunological reagents related to parkin and α-synuclein. Dr. M. Schlossmacher received travel reimbursements from the Michael J. Fox Foundation for Parkinson Research for participation in industry summits and consulting fees as well as royalties from Genzyme-Sanofi for patents unrelated to this work. Dr. G. Toth is an employee and a shareholder of Cantabio Pharmaceuticals. Dr. A. Holmgren (deceased) served as chairman and senior scientist at IMCO Corporation Ltd AB, Stockholm, Sweden. No additional, potentially competing financial interests are declared. Dr. M. Schlossmacher received travel reimbursements from the Michael J. Fox Foundation for Parkinson Research for participation in industry summits and consulting fees as well as royalties from Genzyme-Sanofi for patents unrelated to this work. Dr. G. Toth is an employee and a shareholder of Cantabio Pharmaceuticals. Dr. A. Holmgren (deceased) served as chairman and senior scientist at IMCO Corporation Ltd AB Stockholm Sweden.

Footnotes

  • ↵# Lead contacts: jtomlinson{at}ohri.ca; mschlossmacher{at}ohri.ca

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Age-Associated Insolubility of Parkin in Human Midbrain is Linked to Redox Balance and Sequestration of Reactive Dopamine Metabolites
Jacqueline M. Tokarew, Daniel N. El-Kodsi, Nathalie A. Lengacher, Travis K. Fehr, Angela P. Nguyen, Bojan Shutinoski, Brian O’Nuallain, Ming Jin, Jasmine M. Khan, Andy C. H. Ng, Juan Li, Qiubo Jiang, Mei Zhang, Liqun Wang, Rajib Sengupta, Kathryn R. Barber, An Tran, Stephanie Zandee, Xiajun Dong, Clemens R. Scherzer, Alexandre Prat, Eve Tsai, Masashi Takanashi, Nobutaka Hattori, Jennifer A. Chan, Luigi Zecca, Andrew B. West, Arne Holmgren, Lawrence Puente, Gary S. Shaw, Gergely Toth, John M. Woulfe, Peggy Taylor, Julianna J. Tomlinson, Michael G. Schlossmacher
bioRxiv 2020.11.20.392175; doi: https://doi.org/10.1101/2020.11.20.392175
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Age-Associated Insolubility of Parkin in Human Midbrain is Linked to Redox Balance and Sequestration of Reactive Dopamine Metabolites
Jacqueline M. Tokarew, Daniel N. El-Kodsi, Nathalie A. Lengacher, Travis K. Fehr, Angela P. Nguyen, Bojan Shutinoski, Brian O’Nuallain, Ming Jin, Jasmine M. Khan, Andy C. H. Ng, Juan Li, Qiubo Jiang, Mei Zhang, Liqun Wang, Rajib Sengupta, Kathryn R. Barber, An Tran, Stephanie Zandee, Xiajun Dong, Clemens R. Scherzer, Alexandre Prat, Eve Tsai, Masashi Takanashi, Nobutaka Hattori, Jennifer A. Chan, Luigi Zecca, Andrew B. West, Arne Holmgren, Lawrence Puente, Gary S. Shaw, Gergely Toth, John M. Woulfe, Peggy Taylor, Julianna J. Tomlinson, Michael G. Schlossmacher
bioRxiv 2020.11.20.392175; doi: https://doi.org/10.1101/2020.11.20.392175

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