This preprint is under consideration at Molecular Neurodegeneration. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
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Research article
Xiqun Chen
Massachusetts General Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0001-8582-8891
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor ( MC1R ) and risk of Parkinson disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurotoxicity induced by alpha-synuclein (αSyn), a key player in PD genetics and pathogenesis.
Methods: Nigral dopaminergic neuron toxicity induced by local overexpression of aSyn was assessed in mice that had an inactivating mutation of MC1R , overexpressed its wild-type transgene, or were treated with MC1R agonists. The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in MC1R-mediated protection against αSyn was characterized in vitro . Furthermore, MC1R expression was determined in human postmortem midbrains from patients with PD and unaffected subjects.
Results: Targeted expression of αSyn in the nigrostriatal pathway induced exacerbated synuclein pathologies in MC1R mutant mice, which were accompanied by neuroinflammation and altered Nrf2 responses, and reversed by the human MC1R transgene. Two MC1R agonists were neuroprotective against αSyn-induced dopaminergic neurotoxicity. In vitro experiments showed that Nrf2 was a necessary mediator of MC1R effects. Lastly, MC1R was present in dopaminergic neurons in the human substantia nigra and appeared to be reduced in PD patients.
Conclusion: Our study supports an interaction between MC1R and αSyn that can be mediated by neuronal MC1R through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies for PD.
Keywords
Melanocortin 1 receptor, alpha-synuclein, Parkinson’s disease, melanoma, nuclear factor erythroid 2-related factor 2
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CURRENT STATUS: Under Review
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Review #1 received
Received 07 Apr, 2021
Review #3 received
Received 04 Apr, 2021
Review #2 received
Received 01 Apr, 2021
Reviewer #3 agreed
On 22 Mar, 2021
Reviewer #2 agreed
On 22 Mar, 2021
Reviewer #1 agreed
On 18 Mar, 2021
Review #? received
Received 18 Mar, 2021
Reviewers invited
Invitations sent on 17 Mar, 2021
Editor assigned
On 07 Mar, 2021
Editor invited
On 07 Mar, 2021
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On 04 Mar, 2021
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On 28 Feb, 2021
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Subject Areas
Neurobiology of Disease
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This preprint is under consideration at Molecular Neurodegeneration. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Xiqun Chen
Massachusetts General Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0001-8582-8891
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 12 Mar, 2021
No community comments so far
Review #1 received
Received 07 Apr, 2021
Review #3 received
Received 04 Apr, 2021
Review #2 received
Received 01 Apr, 2021
Reviewer #3 agreed
On 22 Mar, 2021
Reviewer #2 agreed
On 22 Mar, 2021
Reviewer #1 agreed
On 18 Mar, 2021
Review #? received
Received 18 Mar, 2021
Reviewers invited
Invitations sent on 17 Mar, 2021
Editor assigned
On 07 Mar, 2021
Editor invited
On 07 Mar, 2021
Submission checks complete
On 04 Mar, 2021
First submitted
On 28 Feb, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor ( MC1R ) and risk of Parkinson disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurotoxicity induced by alpha-synuclein (αSyn), a key player in PD genetics and pathogenesis.
Methods: Nigral dopaminergic neuron toxicity induced by local overexpression of aSyn was assessed in mice that had an inactivating mutation of MC1R , overexpressed its wild-type transgene, or were treated with MC1R agonists. The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in MC1R-mediated protection against αSyn was characterized in vitro . Furthermore, MC1R expression was determined in human postmortem midbrains from patients with PD and unaffected subjects.
Results: Targeted expression of αSyn in the nigrostriatal pathway induced exacerbated synuclein pathologies in MC1R mutant mice, which were accompanied by neuroinflammation and altered Nrf2 responses, and reversed by the human MC1R transgene. Two MC1R agonists were neuroprotective against αSyn-induced dopaminergic neurotoxicity. In vitro experiments showed that Nrf2 was a necessary mediator of MC1R effects. Lastly, MC1R was present in dopaminergic neurons in the human substantia nigra and appeared to be reduced in PD patients.
Conclusion: Our study supports an interaction between MC1R and αSyn that can be mediated by neuronal MC1R through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies for PD.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
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