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Updated: Dec 25, 2025
Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
Published on: January 7, 2014
BMAL1 regulation of microglia-mediated neuroinflammation in MPTP-induced Parkinson's disease mouse model
Wen-Wen Liu1,2, Shi-Zhuang Wei2, Guo-Dong Huang3
1Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Abstract:
Dysfunction of the circadian rhythm is one of most common nonmotor symptoms in Parkinson's disease (PD), but the molecular role of the circadian rhythm in PD is unclear. We here showed that inactivation of brain and muscle ARNT-like 1 (BMAL1) in 1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine (MPTP)-treated mice resulted in obvious motor functional deficit, loss of dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNpc), decrease of dopamine (DA) transmitter, and increased activation of microglia and astrocytes in the striatum. Time on the rotarod or calorie consumption, and food and water intake were reduced in the Bmal1-/- mice after MPTP treatment, suggesting that absence of Bmal1 may exacerbate circadian and PD motor function. We observed a significant reduction of DANs (~35%) in the SNpc, the tyrosine hydroxylase protein level in the striatum (~60%), the DA (~22%), and 3,4-dihydroxyphenylacetic acid content (~29%), respectively, in MPTP-treated Bmal1-/- mice. Loss of Bmal1 aggravated the inflammatory reaction both in vivo and in vitro. These findings suggest that BMAL1 may play an essential role in the survival of DANs and maintain normal function of the DA signaling pathway via regulating microglia-mediated neuroinflammation in the brain.
Insights
Brain and muscle ARNT-like 1 (BMAL1) inactivation worsens Parkinson's disease motor deficits and dopaminergic neuron loss. BMAL1 deficiency exacerbates neuroinflammation, highlighting its role in Parkinson's disease progression.
Area of Science:
- Neuroscience
- Chronobiology
- Molecular Biology
Background:
- Circadian rhythm dysfunction is a common non-motor symptom in Parkinson's disease (PD).
- The precise molecular mechanisms linking circadian rhythms to PD pathogenesis remain largely unknown.
Purpose of the Study:
- To investigate the role of brain and muscle ARNT-like 1 (BMAL1) in Parkinson's disease.
- To determine if BMAL1 influences motor function, dopaminergic neuron survival, and neuroinflammation in a mouse model of PD.
Main Methods:
- Utilized the 1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine (MPTP) mouse model of Parkinson's disease.
- Compared motor function, dopaminergic neuron counts, dopamine levels, and neuroinflammatory markers in wild-type and Bmal1 knockout mice after MPTP treatment.
Main Results:
- MPTP-treated Bmal1 knockout mice exhibited exacerbated motor deficits, significant loss of dopaminergic neurons in the substantia nigra pars compacta, and reduced dopamine levels.
- Absence of BMAL1 led to increased activation of microglia and astrocytes, indicating aggravated neuroinflammation.
- BMAL1 deficiency worsened both in vivo and in vitro inflammatory responses.
Conclusions:
- BMAL1 plays a crucial role in maintaining the survival of dopaminergic neurons in the substantia nigra.
- BMAL1 is essential for normal dopamine signaling pathway function, potentially through the regulation of microglia-mediated neuroinflammation.
- Targeting BMAL1 may offer a therapeutic strategy for Parkinson's disease by mitigating neuroinflammation and neurodegeneration.
