大野 伸彦

CEP152 is essential for centriole function and neurodevelopment, and pathogenic recessive variants in CEP152 cause primary microcephaly. We identified new compound heterozygous CEP152 variants, c.314 G > A,p.(W105*) and c.2689 A > T,p.(K897*), in a microcephalic patient and analyzed them alongside a homozygous variant c.95 A > C,p.(Q32P) associated with severe microcephaly with marked gyral simplification. In vitro assays revealed distinct effects: p.K897* prevented centrosomal localization, p.W105* led to protein degradation, and p.Q32P retained centrosomal targeting but disrupted binding to Polo-like kinase 4, a key centriole biogenesis kinase and CEP152 partner. In vivo, both Cep152W105*/K897* and Cep152Q32P/Q32P knock-in mice displayed microcephaly; notably, Cep152Q32P/Q32P mice also exhibited severe cortical defects during brain development. Cellular analyses revealed centrosome dysfunction, mitotic errors, and increased apoptosis, which were exacerbated in Cep152Q32P/Q32P brains. Morphological examination, including electron microscopy, further demonstrated structural abnormalities of the centrosomes and centrioles in Cep152Q32P/Q32P brains. Electrophysiological and gene expression analyses confirmed variant-specific neuronal impairments, which correlate with clinical severity. Collectively, these findings demonstrate that distinct CEP152 variants disrupt neurodevelopment through different mechanisms, thereby explaining the spectrum of microcephaly severity and associated phenotypes.

Human activities increasingly disrupt global ecosystems, contributing to climate change, biodiversity loss, and emerging health threats. In response, the One Health framework has gained attention as an integrative approach encompassing human, animal, and environmental health. In a symposium at APPW2025, experts in Exposome science and Digital Transformation discussed how interdisciplinary integration can advance predictive and preventive medicine. This review summarizes five key topics: Exposome as a determinant of disease risk, epigenetic mechanisms encoding environmental memory, environmental programming of brown adipose tissue, adaptive prioritization of environmental signals, and simulation-based drug repurposing. Collectively, these studies highlight a paradigm shift from conventional linear exposure-disease models toward a systems-level understanding integrating cumulative exposures, biological memory, and predictive modeling. The convergence of Exposome science and Digital Transformation provides a foundation for advancing One Health into a predictive and actionable scientific framework.

The ventricular-subventricular zone (V-SVZ) is the largest neurogenic niche in the postnatal mammalian brain, but its organization and migratory dynamics remain poorly understood in gyrencephalic species. Here, we provide ultrastructural and three-dimensional characterization of the V-SVZ neuroblasts in postnatal microminipigs, the smallest pig strain with unique advantages for experimental neuroscience. Transmission electron microscopy revealed developmental changes in cell composition and cytoarchitecture, with migratory neuroblasts consistently associated with glial cells and vasculatures. Notably, serial block-face scanning electron microscopy revealed that tier 3 neuroblasts, a gyrencephalic-specific population, formed elongated, chain-like clusters aligned along vessels, with conserved intracellular features such as polarized organelle distributions and growth cone extension. Radial glial fibers were prominent in neonates but diminished with age, suggesting a developmental shift to vascular scaffolds as primary migration guides. These findings establish microminipigs as a tractable gyrencephalic model for studying postnatal neurogenesis, offering new opportunities for translational research on brain repair.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) develop as spatial pathologies in which neurons and glial cells are interconnected. TAR DNA-binding protein 43 (TDP-43) is a major pathological protein that is inextricably associated with ALS and FTLD. In this study, we investigated the roles of neuronal TDP-43 in neuron-oligodendrocyte interactions using neuron-specific TDP-43 knockout (TDP-43cKO) mice. TDP-43 depletion in neurons induced hypomyelination, which was confirmed by immunohistochemistry and ultrastructural analysis. In addition, conduction disturbance was revealed by electrophysiological analysis. The hypomyelination of TDP-43cKO mouse was restored by cytoplasmic TDP-43 supplementation in neurons. Neuron-specific transcriptome analysis revealed that neurexin 1 (NRXN1) is the regulatory target of TDP-43, which promotes myelin formation. The hypomyelination of TDP-43cKO mice was also restored by NRXN1b supplementation in neurons. We further confirmed that TDP-43 stabilizes Nrxn1 mRNA by binding to the Nrxn1 3'untranslated region (3'UTR). Although TDP-43cKO exhibited impaired recognition memory, the supplementation of NRXN1 in the hippocampus recovered the memory disturbances. In conclusion, this study demonstrates the neuron-oligodendrocyte interaction mediated by neuronal TDP-43 via NRXN1 mRNA stabilization. These findings shed light on neuron-oligodendrocyte interaction in the disease mechanisms of ALS/FTLD.

UNLABELLED: This study investigates the biomechanical properties of primary cilia in healthy kidneys and an early-stage cystic kidney model (CKM), focusing on their role in flow-mediated mechanosensation. Morphological analysis showed that CKM cilia are longer, more curved, and exhibit disrupted axonemal integrity compared with normal cilia. To evaluate the effect of such structural changes on bending and stiffness, which may affect the drag force, shear stress and PC1/PC2 complex activation, we developed a mathematical model simulating urine-flow-induced drag. The model predicts that longer and curved cilia experience only one-fourth of the drag force of shorter and straight cilia under identical flow conditions. Remarkably, addition of 5% glucose to drinking water, which was reported to increase water intake, was predicted by the model to elevate urine flow to levels sufficient to partially normalize ciliary length and tubular morphology in CKM kidneys. These findings indicate that ciliary deformation impairs mechanosensation, contributing to cystogenesis, and that restoring mechanical stimulation may mitigate disease progression. Beyond estimating the urine volume required for therapeutic effect, the model offers a framework for developing interventions targeting ciliary mechanotransduction, which could be particularly useful when fluid-loading strategies are not feasible. This approach highlights the potential of combining morphological analysis, biophysical modeling, and mechanobiology to better understand and treat early cystic kidney disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-39179-y.