Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration

• DOI: 10.1172/jci.insight.162771
• Publication Date: 2023-11-30T17:00:25Z
• Authors: Michael F. Kanan; Patrick W. Sheehan; Jessica N. Haines; Pedro G. Gomez; Adya Dhuler; Collin J. Nadarajah; Zachary M. Wargel; Brittany M. Freeberg; Hemanth R. Nelvagal; Mariko Izumo; Joseph S. Takahashi; Jonathan D. Cooper; Albert A. Davis; Erik S. Musiek
• Keywords: Pars compacta

Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression the core clock gene Bmal1 has been described in patients with PD. BMAL1 required for circadian function but also serves nonrhythmic functions. Germline deletion can cause brain oxidative stress synapse loss mice, it exacerbate dopaminergic neurodegeneration response to toxin MPTP. Here we examined effect cell type-specific on neuron viability vivo. We observed that global, postnatal caused spontaneous tyrosine hydroxylase+ (TH+) neurons substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption behavioral rhythms induced astrocyte- or microglia-specific deletion. However, either pan-neuronal TH neuron-specific cell-autonomous TH+ SNpc. did change percentage after α-synuclein fibril injection, though Bmal1-KO mice had fewer at baseline. Transcriptomics analysis revealed dysregulation pathways involved phosphorylation disease. These findings demonstrate role regulating neuronal survival may have important implications neuroprotection