Lysosomal dysregulation contributes to HAND

溶酶体失调导致 HAND

基本信息

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
项目类别：
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

项目摘要

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作用。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。溶酶体中未消化的产物具有神经毒性，会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 (α-Syn) 聚集，与认知、临床研究中经常观察到帕金森病患者的言语和运动障碍。还表明，大量 HIV-1 感染患者患有神经系统疾病，包括影响步态和身体敏捷性的认知、言语和运动障碍，如帕金森病样症状或然而，所涉及的机制仍不清楚，我们的目标是描述 HIV-1 的特征。降低神经元清除率，导致 HIV 相关神经认知障碍（如运动障碍）的进展我们发现 HIV-1 Vpr 蛋白：(i) 在减少后触发神经元中 α-Syn 的积累。溶酶体酸化；(ii) 通过引起微管活性丧失来破坏细胞器运输； (iii) 解除对溶酶体运动和定位的管制。蛋白质组学分析表明，溶酶体的解除管制。其中包括参与 Vpr 处理的神经元中溶酶体成熟的几种蛋白质的表达水平。 SNAPIN 蛋白调节神经元中的溶酶体酸化、定位和运输。我们建议使用神经元细胞、iPSC 和动物模型来确定 SNAPIN 在其环境中和通过 HIV-1 Vpr（目标 1），因为溶酶体转运到轴突是必要的。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；在存在的情况下识别临床前标记物（旨在恢复 SNAPIN 和溶酶体功能）的方法以及 Vpr 和 SNAPIN 的缺失，并评估神经功能损伤背后的代谢紊乱产生长期的神经学结果（目标 3）。 HIV-1 Vpr 和 SNAPIN 对自噬清除的调节，并强调溶酶体如何重塑 HIV-1 感染期间并影响不同的长寿途径。