Objective: Bmal1 is one of the most important central clock genes of circadian rhythm. Circadian rhythm dysfunction is one of the non-motor symptoms in Parkinson’s disease (PD), however the role of circadian rhythm disorders in Parkinson’s disease is poorly understood. This study aims to investigate whether the deletion of Bmal1 aggravates neuroinflammation to accelerating the dopaminergic cell death in Parkinson’s disease.

Background: Bmal1 is one of the most important central clock genes of circadian rhythm. Circadian rhythm dysfunction is one of the non-motor symptoms in Parkinson’s disease (PD), however the role of circadian rhythm disorders in Parkinson’s disease is poorly understood. This study aims to investigate whether the deletion of Bmal1 aggravates neuroinflammation to accelerating the dopaminergic cell death in Parkinson’s disease.

Methods: In vivo, 6-month-old Bmal1 knockout male mice (Bmal1-/-) were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline. Rotarod test and open field test were used to evaluate motor function. Western blotting was used to detect the TH, Bmal1, Cry1, and Clock level of Striatum and substantia nigra (SN). The inflammatory factors IL-1β, TNF-α, IL-6, and iNOS were detected by real-time RT-PCR. HPLC was used to determine DA and DOPAC levels in striatum. Immunohistochemistry was used to examine DA neurons, microglia, and astrocytes in SN. In vitro, inflammation factors were detected in LPS-treated BV2 cells transfected with Bmal1 siRNA.

Results: The time on the rod was significantly reduced in MPTP-treated Bmal1-/- mice in rotarod test. Compared to the MPTP-treated WT mice, the number of DA neurons in striatum and SN significantly decreased in MPTP-treated Bmal1-/- mice. DA and DOPAC concentration reduced in striatum. Conversely, significantly increased mRNA levels of IL-1β and TNF-α in striatum, and activated microglia and astrocytes in SN were observed. Compared to control group, BV2 cells transfected with Bmal1 siRNA showed obvious inflammatory reaction, accompanied by the increase of IL-1β and TNF-α.

Conclusions: Bmal1 deficiency caused more serious neuroinflammation, exacerbating the MPTP-induced dopaminergic cell death in the progression of Parkinson’s disease.

References: 1. Breen, D.P., et al., Sleep and Circadian Rhythm Regulation in Early Parkinson Disease. Jama Neurology, 2014. 71(5): p. 589-595. 2. Nguyen, K.D., et al., Circadian Gene Bmal1 Regulates Diurnal Oscillations of Ly6C(hi) Inflammatory Monocytes. Science, 2013. 341(6153): p. 1483-1488.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/bmal1-deficiency-aggravates-mptp-induced-dopaminergic-cell-death-through-promoting-neuroinflammation/