Melanocortin 1 receptor activation protects against alpha-synuclein pathologies in models of Parkinson’s disease

Molecular Neurodegeneration

David E. Fisher¹  Yuehang Xu²  Yue Lin²  Danielle Feng²  Xiqun Chen³  Pranay Srivastava³  Michael A. Schwarzschild³  Waijiao Cai⁴  Charles R. Vanderburg⁵  Matthew P. Frosch⁶  Pamela Mclean⁷ 

[1] Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, USA;MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA;MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA;Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, Towson, MD, USA;MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA;Department of Integrative Medicine, HuaShan Hospital, Institutes of Integrative Medicine, Fudan University, Shanghai, China;MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA;Harvard NeuroDiscovery Advanced Tissue Resource Center, Massachusetts General Hospital, Harvard Medical School, Boston, USA;MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA;Harvard NeuroDiscovery Advanced Tissue Resource Center, Massachusetts General Hospital, Harvard Medical School, Boston, USA;Neuropathology Service, Massachusetts General Hospital, Harvard Medical School, Boston, USA;Mayo Clinic, Jacksonville, FL, USA;

关键词: Melanocortin 1 receptor;    Alpha-synuclein;    Parkinson’s disease;    Melanoma;    Nuclear factor erythroid 2-related factor 2;   

DOI  :  10.1186/s13024-022-00520-4

来源: Springer

【 摘 要 】

BackgroundEpidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and risk of Parkinson’s 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.MethodsNigral dopaminergic neuron toxicity induced by local overexpression of aSyn was assessed in mice that have an inactivating mutation of MC1R, overexpress 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 midbrain from patients with PD and unaffected subjects.ResultsTargeted 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 at the tissue level in PD patients.ConclusionOur study supports an interaction between MC1R and αSyn that can be mediated by neuronal MC1R possibly through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies for PD.

【 授权许可】

CC BY