Biology subjects

Sati, A.

Publications and source records attributed to Sati, A..

3 recordsLinked to original sources

bioRxiv2026

ATP13A2 Loss of Function-Driven Polyamine Dysregulation Induces SAM Depletion and Epigenetic Astrocyte Toxicity

Aging is the strongest risk factor for neurodegeneration, yet how the human brain ages remains poorly understood. Loss-of-function (LOF) variants in ATP13A2 cause severe juvenile-onset Parkinsons disease, providing a window into the mechanisms that accelerate age-related neurodegeneration. ATP13A2-LOF causes lysosomal polyamine sequestration, but how this promotes pathogenesis remains unclear. We discovered that ATP13A2-LOF depletes cytosolic polyamines in astrocytes, triggering compensatory upregulation of de novo polyamine biosynthesis, which diverts S-adenosyl methionine (SAM) from DNA and histone methylation, leading to increased chromatin accessibility and epigenetic reprogramming of astrocytes into a neuroinflammatory state that releases neurotoxic cytokines that promote dopaminergic neuron death. In ATP13A2 knockout mice and human models, we find that genetic and pharmacological inhibition of SAM utilization in polyamine biosynthesis prevents astrocytic epigenetic reprogramming and promotes dopaminergic neuron survival. These findings reveal a direct link between polyamine metabolism, epigenetic dysfunction, and neurotoxic inflammation, uncovering new therapeutic opportunities in Parkinsons disease.

neuroscience↗

bioRxiv2025

Druggable genome CRISPRi screen in 3D hydrogels reveals regulators of cortactin-driven actin remodeling in invading glioblastoma cells

To identify new therapeutic targets that limit glioblastoma (GBM) invasion, we applied druggable-genome CRISPR screens to patient-derived GBM cells in micro-dissectible biomimetic 3D hydrogel platforms that permit separation and independent analysis of core vs. invasive fractions. We identified 12 targets whose suppression limited invasion, of which ACP1 (LMW-PTP) and Aurora Kinase B (AURKB) were validated in neurosphere assays. Proximity labeling analysis identified cortactin as an ACP1- AURKB link, as cortactin undergoes serine phosphorylation by AURKB and tyrosine dephosphorylation by ACP1. Suppression of ACP1 or AURKB in culture and in vivo shifted the balance of cortactin phosphorylation in GBM and reduced actin polymerization and actin-cortactin co-localization. Additional biophysical analysis implicated AURKB in GBM cell adhesion and cortical stiffness, and ACP1 in resistance to mechanical stress and shape plasticity needed for 3D migration. These findings reveal a novel targetable axis that balances kinase and phosphatase activities to regulate actin polymerization during GBM invasion.

cancer biology↗

bioRxiv2022

Liver sinusoidal endothelial cells orchestrate NK cell recruitment and activation in acute inflammatory liver injury

In both steady-state and during endotoxicosis, liver sinusoidal endothelial cells (LSECs) can rapidly clear lipopolysaccharide (LPS) from the bloodstream. They are located along blood sinusoids of the liver, and establish intimate contact with circulating and tissue-resident immune cells. However, their role in regulating immune responses during LPS-induced endotoxicosis remains poorly understood. Here, we show that LSECs play a dual role in regulating inflammatory responses, acting as modulators of NK cell pro-inflammatory output and as major producers of immune cell-attracting chemokines. We demonstrate that LSECs switch their chemokine expression pattern driven by LPS and IFN-{gamma}, resulting in the production of the myeloid-attracting chemokine CCL2 and the lymphoid-attracting chemokine CXCL10, which accumulate in the serum of LPS-challenged animals. In livers of LPS-injected mice, monocytes and Kupffer cells expressed highest amounts of the pro-inflammatory cytokine Il12a and Il18 transcripts, while NK cells expressed the highest amounts of Ifng. NK cell exposure to LSECs in vitro led to global transcriptomic changes, and primed NK cells to produce higher amounts of IFN-{gamma} in response to IL-12 and IL-18. LSECs required exposure to IFN-{gamma} for Cxcl10 expression, and Cxcl10 gene-deletion in endothelial cells abrogated NK cell accumulation in the liver after LPS treatment. Thus, our data indicate that LSECs occupy a unique temporal and spatial position acting as central regulators that respond to both LPS and immune-derived inflammatory signals, and fuel a positive feedback loop of immune cell attraction and activation in the inflamed liver tissue. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/500206v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@653c53org.highwire.dtl.DTLVardef@5ba4bdorg.highwire.dtl.DTLVardef@9caad8org.highwire.dtl.DTLVardef@1945eb5_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗