Sawaya Bassel E, Santerre Maryline
Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine and Department of Neurology Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Department of Neurology Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
bioRxiv. 2025 Jul 16:2025.07.11.664248. doi: 10.1101/2025.07.11.664248.
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 (CK1δ) as a central mediator of this dysfunction, acting via phosphorylation of the adaptor 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 novel Vpr-CK1δ-SNAPIN axis contributing to HAND and highlight lysosomal transport as a targetable mechanism in neurodegeneration.
尽管接受了抗逆转录病毒治疗（ART），但在近40%病毒得到抑制的个体中，HIV相关神经认知障碍（HAND）仍然存在。溶酶体功能障碍已成为HAND发病机制的关键因素，然而，将慢性HIV暴露与神经元降解受损联系起来的分子机制仍未完全明确。在此，我们确定HIV-1病毒蛋白R（Vpr）是神经元溶酶体酸化失败、聚集和降解受损的驱动因素。我们发现酪蛋白激酶1δ（CK1δ）是这种功能障碍的核心介质，它通过对接蛋白SNAPIN的磷酸化发挥作用。Vpr诱导的CK1δ激活导致SNAPIN过度磷酸化，破坏溶酶体的定位和运动。通过选择性抑制CK1δ可挽救这些缺陷，恢复溶酶体酸化、定位和线粒体自噬。我们的研究结果确定了一个导致HAND的新的Vpr-CK1δ-SNAPIN轴，并突出了溶酶体运输作为神经退行性变中一个可靶向的机制。
