Santerre, M. | bioRxiv Science

bioRxiv2025

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

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

neuroscience↗

bioRxiv2020

HIV-1 gp120 impairs spatial memory through CREB

HIV-associated neurocognitive disorders (HAND) remains an unsolved problem in the clinical management of HIV-1 carriers, because existing anti-retroviral therapy while suppressing viral replication, do not prevent neurocognitive impairment (e.g. spatial memory loss). HIV-1 gp120 protein has been proposed to contribute to HAND because it is shed by infected cells and the use of antibodies revealed its presence in cerebrospinal fluid (CSF) even in the combinatory antiretroviral therapy (cART) era. The cyclic AMP response element-binding protein (CREB) has long been known to be a star player in memory. CREB exerts its effect partially through regulating the genes for peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 and brain-derived neurotrophic factor (BDNF). CREB, PGC-1, and BDNF levels are low in the brains of patients with neurodegenerative diseases and a dearth of either protein is associated with cognitive decline. We have obtained data showing that gp120 contributes to neurodegeneration by altering CREB phosphorylation on serine residue 133 thus disrupting mitochondrial movement and synaptic plasticity leading to spatial memory loss. Inhibition of CREB function was also associated with a decrease of ATP levels and lower mitochondrial DNA copy numbers. Our data was validated in vitro (primary mouse neurons and neuronal cell line, SH-SY5Y) and in vivo (gp120-tg mice and mice injected with gp120). The negative effect of gp120 was alleviated in cells and animals in the presence of Rolipram. Hence, we conclude that HIV-1 gp120 protein contributes to spatial memory impairment via inhibition of CREB protein activity.

neuroscience↗