# CK1δ-dependent SNAPIN dysregulation drives lysosomal failure in HIV-1 Vpr-exposed neurons: A targetable mechanism in HAND

## TL;DR

This study identifies a new mechanism involving HIV-1 Vpr, CK1δ, and SNAPIN that causes lysosomal dysfunction in neurons, offering a potential treatment target for HIV-associated neurocognitive disorders.

## Contribution

The paper discovers a novel Vpr-CK1δ-SNAPIN pathway linking HIV exposure to lysosomal failure in neurons, suggesting a targetable mechanism for HAND.

## Key findings

- Vpr induces CK1δ activation, leading to SNAPIN hyperphosphorylation and lysosomal dysfunction.
- CK1δ inhibition rescues lysosomal acidification, motility, and mitophagy in Vpr-exposed neurons.
- SNAPIN Ser50 phosphorylation is critical for Vpr-induced lysosomal clustering.

## Abstract

HIV-associated neurocognitive disorders (HANDs) 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 report casein kinase 1 delta (CK1δ) as a central mediator of this dysfunction, acting via phosphorylation of the adapter protein SNAPIN. Vpr-induced CK1δ activation leads to hyperphosphorylation of SNAPIN, disrupting lysosomal positioning and motility. These defects are rescued by selective CK1δ inhibition, which restores lysosomal acidification, positioning, and mitophagy. Our findings define a Vpr-CK1δ-SNAPIN axis that contributes to HANDs and highlight lysosomal transport as a targetable mechanism in neurodegeneration.

•Vpr promotes CK1δ-dependent SNAPIN disruption and lysosomal dysfunction•CK1δ inhibition restores lysosomal acidification, motility, and mitophagy•SNAPIN Ser50 phosphorylation mediates Vpr-induced lysosomal clustering•CK1δ-SNAPIN axis reveals a targetable mechanism in HAND neurodegeneration

Vpr promotes CK1δ-dependent SNAPIN disruption and lysosomal dysfunction

CK1δ inhibition restores lysosomal acidification, motility, and mitophagy

SNAPIN Ser50 phosphorylation mediates Vpr-induced lysosomal clustering

CK1δ-SNAPIN axis reveals a targetable mechanism in HAND neurodegeneration

Biochemistry; Pharmacology; Virology