Primary cilia have recently been identified in mammalian spermatocytes, but their developmental regulation during testicular maturation remains poorly understood. Here, we investigate the dynamics of ciliogenesis during mouse puberty and show that primary cilia are not an intrinsic feature of spermatocytes during the first wave of meiosis, initiated at 8 days post partum (dpp). Ciliogenesis begins only at day 20 dpp, where cilia are detected across all stages of prophase I, indicating no direct association with synapsis or desynapsis. We further found that Aurora kinase A is associated with cilia disassembly in late diplotene and that spermatocytes retaining a polymerized cilium fail to assemble a bipolar spindle. In addition, proteomic analysis defined the 19–21 dpp period as a key developmental window associated with ciliogenesis and flagellogenesis. We also identified ciliated spermatocytes in the human testis, providing the first evidence of meiotic cilia in human meiocytes. This work reveals that ciliogenesis is a developmentally regulated process during testicular maturation in mouse.
I. Pérez-Moreno, P. López-Jiménez, H. Zapata-Polo et al.· Frontiers in Cell and Develo...· 0 citations
Transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological hallmark of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Modulation of TDP-43 pathology represents a promising disease-modifying strategy. Tau tubulin kinase 1 (TTBK1) has emerged as a relevant therapeutic target; however, selectivity over the TTBK2 isoform is required to avoid ciliogenesis-related liabilities. Here, we report the discovery of selective, brain-penetrant TTBK1 inhibitors through a structure-guided medicinal chemistry program. Lead compounds exhibit potent and selective TTBK1 inhibition, no impact on ciliogenesis, and central nervous system exposure. We found that these inhibitors reduce TDP-43 phosphorylation levels in neuroblastoma cells and FTD patient-derived models. The optimized lead compound demonstrated a brain-to-plasma ratio of 3:1, a maximum tolerated dose, and a wide therapeutic window. In vivo, administration restored cognitive deficits, conferred neuroprotection in the frontal cortex, and reduced microglial activation in an FTD-TDP mouse model, supporting its therapeutic potential.
Cecilia Sanchez-Santos, Alberto Jiménez-Amor, Loreto Martínez-González et al.· Journal of Medicinal Chemist...· 0 citations
