Lysosomal dysregulation contributes to HAND

溶酶体失调导致 HAND

• 批准号: 10886233
• 负责人: Maryline Santerre
• 金额: $ 53.46万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10886233
• 关键词: AIDS dementia; Affect; Animal Model; Area; Autophagocytosis; Autophagosome; Axon; Binding; Biological Assay; Biological Models; Brain; Cell physiology; Cells; Clinical Research; Cognition Disorders; Complex; Cytoplasm; Degradation Pathway; Disease; Environment; Exhibits; Functional disorder; Gait; Goals; HIV; HIV-1; HIV-associated neurocognitive disorder; HIV/AIDS; Hand; Homeostasis; Hydrolase; Impairment; Incidence; Infection; Ions; Life Expectancy; Lipids; Longevity; Lysosomes; Mediating; Metabolic; Methods; Microtubules; Movement; Movement Disorders; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurological outcome; Neurons; Nuclear; Nutrient; Organelles; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Persons; Play; Positioning Attribute; Post-Translational Regulation; Premature aging syndrome; Prevalence; Process; Proteins; Proteolysis; Proteome; Proteomics; Regulation; Retroviridae; Role; SNAP receptor; SNAPIN gene; Shapes; Sorting; Speech Disorders; Substantia nigra structure; Symptoms; Synaptic Vesicles; Virus; Virus Diseases; Western Blotting; alpha synuclein; antiretroviral therapy; cell type; combinatorial; dopaminergic neuron; improved; in vitro Model; induced pluripotent stem cell; late endosome; link protein; loss of function; metabolome; metabolomics; misfolded protein; motor disorder; multiple omics; nervous system disorder; neuropathology; neurotoxic; phosphoproteomics; pre-clinical; presynaptic neurons; prevent; protein aggregation; protein degradation; protein function; proteostasis; retrograde transport; therapeutic biomarker; therapeutic target; trafficking; vpr Gene Products; wasting

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.

摘要 溶酶体功能对于保护神经元的内稳态是必不可少的。精确的溶酶体活动和 动力学对于维持脂质、错误折叠的蛋白质和受损细胞器的降解至关重要。 溶酶体的未消化产物具有神经毒性，导致神经退行性疾病。 溶酶体功能障碍可导致α-突触核蛋白(-Syn)聚集，与认知、 帕金森氏症患者常可观察到言语、运动障碍。临床研究 还显示，相当数量的HIV-1感染患者患有神经系统疾病，包括 影响步态和身体灵活性的认知、言语和运动障碍，如帕金森样症状或 帕金森症。然而，其中涉及的机制仍不清楚。我们的目标是描述HIV-1是如何 减少神经元清除导致HIV相关神经认知障碍的进展，如运动 功能障碍。我们发现，HIV-1Vpr蛋白：(I)在减少-Syn后，触发神经元内的HIV一Syn积聚 溶酶体的酸化；(Ii)通过引起微管活性的丧失而扰乱细胞器的运输； 以及(Iii)解除对溶酶体运动和定位的管制。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的表达水平。其中包括 管理蛋白调节溶酶体的酸化、定位和神经元运输的管理蛋白因此， 使用神经细胞、ipscs和一个动物模型，我们建议确定翻译后调节。 其环境中的Snapin和艾滋病毒-1 VPR(目标1)。因为溶酶体进入轴突的运输是必要的 为了有效地降解，我们将探索VPR诱导的Snapin失调对溶酶体运输的影响 (目标2)。最后，溶酶体降解是蛋白质动态平衡的重要组成部分；我们将使用多组学 识别临床前标志物(旨在恢复管理单元和溶酶体功能)的方法 以及VPR和Snapin的缺失，并评估神经损伤的代谢障碍 导致长期的神经结果(目标3)。这项研究将使人们更好地理解 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 在感染HIV-1期间，并影响不同的长寿途径。