Quintremil, S. | bioRxiv Science

bioRxiv2023

The Nucleoporin Nup153 Is the Anchor for Kif1a during Basal Nuclear migration in Brain Progenitor Cells

Radial glial progenitors (RGPs) are highly elongated epithelial cells that give rise to most stem cells, neurons, and glia, in the vertebrate cerebral cortex. During development the RGP nuclei exhibit a striking pattern of cell cycle-dependent oscillatory movements known as interkinetic nuclear migration (INM), which we previously found to be mediated during G1 by the kinesin Kif1a, and during G2 by cytoplasmic dynein, recruited to the nuclear envelope by the nucleoporins RanBP2 and Nup133. We now identify Nup153 as a nucleoporin anchor for Kif1a, responsible for G1-specific basal nuclear migration, providing a complete model for the mechanisms underlying this basic, but mysterious behavior, with broad implications for understanding brain development.

neuroscience↗

bioRxiv2018

Endo-lysosomal sorting and degradation of Tau mediates glucocorticoid-driven hippocampalmalfunction

Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimers disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD, and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.

neuroscience↗