Abstract
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.
Highlights
Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and risk of Parkinson’s disease (PD)
MC1R disruption exacerbates synucleinopathies in the nigrostriatal pathway in αSyn associated virus (AAV)‐injected mice Our previous study demonstrates that the nigrostriatal dopaminergic pathway is compromised under basal conditions in MC1R extension (MC1Re/e) mice carrying a loss-of-function gene mutation and exhibiting blond-red fur [20]
By using genetic and pharmacological approaches, our study demonstrated in multiple in vivo and in vitro models that MC1R loss-of-function leads to exacerbated PD-associated αSyn pathologies
Summary
Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and risk of Parkinson’s disease (PD). Various cellular events including proteinopathy, neuroinflammation, and oxidative stress contribute to the degenerative process, leading to the eventual loss of dopaminergic neurons of the nigrostriatal dopaminergic pathway of the brain, another pathological hallmark of PD [3]. Severe loss-of-function polymorphisms of MC1R contributes to red hair/fair skin and are associated with skin aging, and melanoma risk [8,9,10]. More recent studies identify a critical role of MC1R in regulating physiological functions in the skin including the immune response, DNA repair, and cell differentiation and proliferation, which can be pigmentation-dependent or -independent [10, 11]. In addition to its cutaneous expression and function, MC1R is expressed in other tissue and cell types, including immune and endothelial cells, and can modulate the immune system and inflammatory response [12, 13]. α-MSH or its synthetic analog N le4,D-Phe7-α-MSH (NDP-MSH), a tanning agent and drug approved by the European Medicines Agency for treating the photosensitive skin condition erythropoietic porphyria [14], exerts protective effects in models of ischemic stroke, traumatic brain injury, spinal cord injury, Alzheimer’s disease, and neuroinflammatory disease [15,16,17,18], with MC1R engagement shown to mediate this protection in the latter model
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