| Autor: |
Kanan MF; Department of Neurology and., Sheehan PW; Department of Neurology and., Haines JN; Department of Neurology and., Gomez PG; Department of Neurology and., Dhuler A; Department of Neurology and., Nadarajah CJ; Department of Neurology and., Wargel ZM; Department of Neurology and., Freeberg BM; Department of Neurology and., Nelvagal HR; Departments of Pediatrics, Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Izumo M; Department of Neuroscience and., Takahashi JS; Department of Neuroscience and.; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Cooper JD; Departments of Pediatrics, Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Davis AA; Department of Neurology and., Musiek ES; Department of Neurology and.; Center On Biological Rhythms and Sleep (COBRAS), Washington University School of Medicine, St. Louis, Missouri, USA. |
| Abstrakt: |
Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after α-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD. |
