Lysosomal dysregulation contributes to HAND

总结 溶酶体功能对于保护神经元稳态是必不可少的。精确的溶酶体活性， 动力学对于维持脂质、错误折叠蛋白质和受损细胞器的降解至关重要。 来自溶酶体的未消化产物是神经毒性的，并且是神经退行性疾病的原因。 溶酶体功能障碍可导致α-突触核蛋白（α-Syn）聚集，与认知， 语言和运动障碍，常在患有帕金森病的患者中观察到。临床研究 还表明，相当数量的HIV-1感染者患有神经系统疾病，包括 认知，言语和运动障碍，影响他们的步态和身体敏捷性，如帕金森样症状或 帕金森症。然而，所涉及的机制仍不清楚。我们的目标是描述HIV-1 降低神经元清除率，导致HIV相关神经认知障碍（如运动障碍）的进展 功能障碍我们发现，HIV-1 Vpr蛋白：（i）在减少神经元中的β-Syn后， 溶酶体酸化;（ii）通过引起微管活性的丧失而破坏细胞器运输; 和（iii）解除对溶酶体运动和定位的调节。蛋白质组学分析显示， 在Vpr处理的神经元中参与溶酶体成熟的几种蛋白质的表达水平。其中之一是 调节神经元中溶酶体酸化、定位和运输的SNAPIN蛋白。因此，我们认为， 使用神经元细胞，iPSC和动物模型，我们建议确定的翻译后调节， SNAPIN在其环境和HIV-1 Vpr（目的1）。由于溶酶体进入轴突的运输是必要的 为了有效降解，我们将探讨Vpr诱导的SNAPIN失调对溶酶体转运的影响 (Aim 2）。最后，溶酶体降解是蛋白质稳态的重要组成部分;我们将使用多组学方法， 方法来鉴定临床前标志物（旨在恢复SNAPIN和溶酶体功能）， 以及Vpr和SNAPIN的缺乏，并评估神经损伤的代谢紊乱 导致长期神经学结果（目标3）。这项研究将使人们更好地了解一般 HIV-1 Vpr和SNAPIN对自噬清除的调节，并强调溶酶体是如何重塑的 并影响不同的长寿促进途径。

SUMMARY The lysosomal function is essential for protecting neuronal homeostasis. A precise lysosome activity and dynamics are crucial to maintaining the degradation of lipids, misfolded proteins, and damaged organelles. Undigested products from the lysosome are neurotoxic and responsible for neurodegenerative diseases. Lysosomal dysfunction can lead to the aggregation of alpha-synuclein (-Syn), associated with cognitive, speech, and movement disorders often observed in patients suffering from Parkinson's disease. Clinical studies also showed that a significant number of HIV-1 infected patients suffer from neurological disorders, including cognitive, speech, and motor disorders that affect their gait and body agility, like parkinsonian-like symptoms or Parkinsonism. However, the mechanisms involved remain unclear. Our goal is to characterize how HIV-1 decreases neuronal clearance leading to a progression of HIV-associated neurocognitive disorders like motor dysfunction. We showed that HIV-1 Vpr protein: (i) triggers the accumulation of -Syn in neurons after decreasing the lysosomal acidification; (ii) disrupts the organelles trafficking by provoking the loss of microtubules activity; and (iii) deregulates the lysosome movement and positioning. Proteomic analysis showed deregulation in the expression levels of several proteins involved in lysosomal maturation in Vpr-treated neurons. Among these is the SNAPIN protein that regulates lysosomal acidification, positioning, and trafficking in neurons. Therefore, using neuronal cells, iPSCs, and an animal model, we propose to determine the post-translational regulation of SNAPIN in its environment and by HIV-1 Vpr (Aim 1). Since the transport of lysosomes into the axon is necessary for efficient degradation, we will explore the impact of Vpr-induced SNAPIN dysregulation on lysosomal transport (Aim 2). Finally, lysosomal degradation is an essential part of protein homeostasis; we will use a multi-omics approach to identify pre-clinical markers (that aim to restore SNAPIN and lysosomal functions) in the presence and absence of Vpr and SNAPIN and assess the metabolic disturbances underlying neurological impairment resulting in long-term neurological outcomes (Aim 3). This study will bring a better understanding of the general regulation of the autophagic clearance by HIV-1 Vpr and SNAPIN and highlight how lysosomes are reshaped during HIV-1 infection and affect different longevity-promoting pathways.