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bioRxiv · 10.1101/2025.07.11.664248

CK1δ-Dependent SNAPIN Dysregulation Drives Lysosomal Failure in HIV-1 Vpr-Exposed Neurons: A Targetable Mechanism in HAND

Sawaya, B. E.·Santerre, M.
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Abstract

HIV-associated neurocognitive disorders (HAND) persist in nearly 40% of virally suppressed individuals despite antiretroviral therapy (ART). Lysosomal dysfunction has emerged as a key contributor to HAND pathogenesis, yet the molecular mechanisms linking chronic HIV exposure to impaired neuronal degradation remain incompletely defined. Here, we identify HIV-1 Viral Protein R (Vpr) as a driver of lysosomal acidification failure, clustering, and degradative impairment in neurons. We uncovered casein kinase 1 delta (CK1{delta}) as a central mediator of this dysfunction, acting via phosphorylation of the adaptor protein SNAPIN. Vpr-induced CK1{delta} activation leads to hyperphosphorylation of SNAPIN, disrupting lysosomal positioning and motility. These defects are rescued by selective CK1{delta} inhibition, which restores lysosomal acidification, positioning, and mitophagy. Our findings define a novel Vpr-CK1{delta}-SNAPIN axis contributing to HAND and highlight lysosomal transport as a targetable mechanism in neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/664248v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@128db49org.highwire.dtl.DTLVardef@154d5d1org.highwire.dtl.DTLVardef@a18f13org.highwire.dtl.DTLVardef@b82ac5_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Sawaya, B. E., Santerre, M.. 2025-07-16. CK1δ-Dependent SNAPIN Dysregulation Drives Lysosomal Failure in HIV-1 Vpr-Exposed Neurons: A Targetable Mechanism in HAND. https://doi.org/10.1101/2025.07.11.664248

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