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.

概括 溶酶体功能对于保护神经元稳态至关重要。精确的溶酶体活性和 动力学对于维持脂质，错误折叠蛋白和受损细胞器的降解至关重要。 来自溶酶体的未消除产物是神经毒性的，负责神经退行性疾病。 溶酶体功能障碍会导致与认知能力相关的α-核蛋白（-Syn）的聚集 患有帕金森氏病的患者经常观察到言语和运动障碍。临床研究 还表明，大量的HIV-1感染患者患有神经系统疾病，包括 影响其敏捷性和身体敏捷性的认知，语音和运动障碍，例如帕金森氏症符号或 帕金森主义。但是，涉及的机制尚不清楚。我们的目标是表征HIV-1如何 降低神经元清除，导致与运动等艾滋病毒相关的神经认知疾病的进展 功能障碍。我们证明了HIV-1 VPR蛋白：（i）降低后，触发神经元中-Syn的积累 溶酶体酸化； （ii）通过引起微管活动的损失来破坏细胞器的运输； （iii）消除溶酶体运动和定位。蛋白质组学分析表明在 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。其中是 调节神经元中溶酶体酸化，定位和运输的Snapin蛋白。所以， 使用神经元细胞，IPSC和动物模型，我们建议确定翻译后调节 Snapin在其环境中和HIV-1 VPR（AIM 1）。由于溶酶体进入轴突是必要的 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 （目标2）。最后，溶酶体降解是蛋白质稳态的重要组成部分。我们将使用多摩斯 在存在下识别临床前标记（旨在恢复Snapin和溶酶体功能）的方法 缺乏VPR和Snapin以及评估神经系统损害的代谢灾害 导致长期神经系统结果（AIM 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，并突出显示如何重塑溶酶体 在HIV-1感染期间，影响不同的寿命促进途径。