Zachary M. Wargel

APOE genotype regulates disease development in mouse models of α-synucleinopathy and affects cognition in patients with Parkinson’s disease.

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.

Atypical teratoid/rhabdoid tumor (ATRT) is a rare, highly aggressive embryonal central nervous system (CNS) neoplasm of infancy and childhood. Since its recognition as a distinct entity in the late 20th century, breakthroughs in molecular pathology and neuroimaging have transformed diagnostic, prognostic, and therapeutic paradigms. This review synthesizes historical milestones, pathology and molecular biology, radiologic hallmarks, and advances of the past five years, with special emphasis on the WHO 2021 CNS tumor classification. We also highlight institutional experience at St. Louis Children’s Hospital (SLCH), where systematic data collection and volumetric analyses underscore the challenges and opportunities in modern ATRT care.