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Updated: Jul 8, 2025
Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
Published on: January 7, 2014
Peripheral MC1R Activation Modulates Immune Responses and is Neuroprotective in a Mouse Model of Parkinson's Disease
Pranay Srivastava1,2, Shuhei Nishiyama1, Fang Zhou1,2
1MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Background:
Melanocortin 1 receptor (MC1R) is a key pigmentation gene, and loss-of-function of MC1R variants that produce red hair may be associated with Parkinson's disease (PD). We previously reported compromised dopaminergic neuron survival in Mc1r mutant mice and dopaminergic neuroprotective effects of local injection of a MC1R agonist to the brain or a systemically administered MC1R agonist with appreciable central nervous system (CNS) permeability. Beyond melanocytes and dopaminergic neurons, MC1R is expressed in other peripheral tissues and cell types, including immune cells. The present study investigates the impact of NDP-MSH, a synthetic melanocortin receptor (MCR) agonist that does not cross BBB, on the immune system and the nigrostriatal dopaminergic system in mouse model of PD.
Methods:
C57BL/6 mice were treated systemically with MPTP.HCl (20 mg/kg) and LPS (1 mg/kg) from day 1 to day 4 and NDP-MSH (400 µg/kg) or vehicle from day 1 to day 12 following which the mice were sacrificed. Peripheral and CNS immune cells were phenotyped and inflammatory markers were measured. The nigrostriatal dopaminergic system was assessed behaviorally, chemically, immunologically, and pathologically. To understand the role of regulatory T cells (Tregs) in this model, CD25 monoclonal antibody was used to deplete CD25 + Tregs.
Results:
Systemic NDP-MSH administration significantly attenuated striatal dopamine depletion and nigral dopaminergic neuron loss induced by MPTP + LPS. It improved the behavioral outcomes in the pole test. Mc1r mutant mice injected with NDP-MSH in the MPTP and LPS paradigm showed no changes in striatal dopamine levels suggesting that the NDP-MSH acts through the MC1R pathway. Although no NDP-MSH was detected in the brain, peripheral, NDP-MSH attenuated neuroinflammation as observed by diminished microglial activation in the nigral region, along with reduced TNF-α and IL1β levels in the ventral midbrain. Depletion of Tregs was associated with diminished neuroprotective effects of NDP-MSH.
Conclusions:
Our study demonstrates that peripherally acting NDP-MSH confers protection on dopaminergic nigrostriatal neurons and reduces hyperactivated microglia. NDP-MSH modulates peripheral immune responses, and Tregs may be involved in the neuroprotective effect of NDP-MSH.
Insights
Peripheral administration of NDP-MSH protects against Parkinson's disease (PD) by reducing neuroinflammation and dopaminergic neuron loss. This effect is mediated through the Melanocortin 1 Receptor (MC1R) pathway and involves regulatory T cells (Tregs).
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Melanocortin 1 receptor (MC1R) is crucial for pigmentation and linked to Parkinson's disease (PD).
- Loss-of-function MC1R variants (red hair) may increase PD risk.
- Previous studies showed MC1R agonists protect dopaminergic neurons.
Purpose of the Study:
- Investigate the impact of NDP-MSH, a peripheral MC1R agonist, on the immune and nigrostriatal dopaminergic systems in a mouse model of PD.
- Determine if NDP-MSH exerts neuroprotection via the MC1R pathway.
- Explore the role of regulatory T cells (Tregs) in NDP-MSH's effects.
Main Methods:
- Mice received MPTP and LPS to model PD, treated with systemic NDP-MSH or vehicle.
- Immune cells and inflammatory markers were analyzed peripherally and in the CNS.
- Dopaminergic system integrity was assessed behaviorally, chemically, and pathologically.
- Regulatory T cells (Tregs) were depleted using anti-CD25 antibody.
Main Results:
- Systemic NDP-MSH significantly reduced striatal dopamine depletion and dopaminergic neuron loss.
- NDP-MSH improved behavioral outcomes in the pole test.
- Neuroprotection was dependent on MC1R, as NDP-MSH had no effect in Mc1r mutant mice.
- Peripheral NDP-MSH attenuated neuroinflammation, reducing microglial activation and inflammatory cytokines (TNF-α, IL1β) in the brain.
- Depletion of Tregs diminished the neuroprotective effects of NDP-MSH.
Conclusions:
- Peripherally administered NDP-MSH protects nigrostriatal dopaminergic neurons and reduces neuroinflammation.
- NDP-MSH modulates peripheral immune responses, potentially involving Tregs.
- The findings highlight a novel therapeutic strategy for PD targeting peripheral MC1R activation.
