Alpha-Synuclein aberrantly modifies the nanoscale distribution and function of ion channels to promote neuronal cytotoxicity

α-突触核蛋白异常地改变离子通道的纳米级分布和功能以促进神经元细胞毒性

• 批准号: 10635208
• 负责人: Eamonn James Dickson
• 金额: $ 165.05万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635208
• 关键词: Action Potentials; Address; Affect; Age; Alzheimer' s disease related dementia; Apoptosis; Behavior; Biochemistry; Bioenergetics; Biological Assay; Biophysics; Buffers; Cell Death; Cell membrane; Cell physiology; Cells; Cellular biology; Data; Deposition; Development; Disease; Disease Progression; Electrophysiology (science); Endoplasmic Reticulum; Enzymes; Frequencies; Functional disorder; Generations; Genetic; Goals; Health; Health Care Costs; Homeostasis; Idiopathic Parkinson Disease; Image; Individual; Inherited; Investigation; Ion Channel; Knowledge; Lead; Lewy Bodies; Lewy neurites; Life Expectancy; Link; Lipids; Mediating; Medicine; Membrane; Mission; Mitochondria; Modeling; Molecular; Movement; Mutation; Necrosis; Neurodegenerative Disorders; Neurons; Neurosciences; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Physiological; Point Mutation; Potassium; Potassium Channel; Prevalence; Production; Property; Proteins; Public Health; Reporting; Risk Factors; Role; SNCA gene; Signal Transduction; Site; Substantia nigra structure; Testing; Therapeutic; United States; United States National Institutes of Health; Work; alpha synuclein; cytotoxic; cytotoxicity; density; deviant; dopaminergic neuron; genome wide association study; health goals; innovation; insight; lipidomics; mitochondrial membrane; motor symptom; nano; nanocomplexes; nanoscale; neuron loss; neuropathology; neurotoxic; neurotoxicity; novel; novel strategies; patch clamp; programs; superresolution imaging; synucleinopathy; therapeutic development; therapeutic target; treatment strategy; voltage

Project Summary Alpha-synuclein (α-syn) is a neuronal protein encoded by the SNCA gene. Genetically, mutations in the SNCA gene lead to enhanced expression and aggregation of α-synuclein and cause inherited forms of Parkinson’s disease (PD). In idiopathic PD, as well as Alzheimer’s disease and related dementias (ADRD), α-syn aggregation leads to the formation of toxic α-syn fibrils that constitute the building blocks of Lewy bodies, the deviant protein deposits that accumulate and are associated with neuronal cell death. Thus, α-syn is considered a key pathological hallmark of PD. Due to our ever-extending life expectancy, the prevalence of PD is estimated to double by 2030. Age is the strongest risk factor for its development, and currently there is no cure and no therapeutic known to modify disease progression. Despite clear neuropathological consequences for α-syn accumulation in PD and ADRD there is a lack of mechanistic intracellular information regarding the molecular pathways perturbed by α-syn that lead to cell death. The goal of this application is to explore this critical gap in knowledge by examining whether α-syn alters the molecular composition of membrane contact sites. Our central hypothesis is that α-syn aberrantly remodels plasma membrane ion channels and lipids to alter endoplasmic reticulum – mitochondrial Ca2+ nanodomains leading to neurotoxicity. Our data supports the concept that PD is a nanostructural disease. To test this hypothesis, we implement an innovative multi-scale (including lipidomics, super-res imaging, genetics, and patch-clamp electrophysiology) approach to vertically integrate signaling cascades from the level of single lipids to neuronal networks, with the goal of providing fundamental knowledge that will aid in the development of novel strategies that slow or reduce neurotoxic α-syn-mediated cell death. Specific Aim 1 tests the hypothesis that α-syn remodels voltage-gated potassium and Ca2+ nanocomplexes to alter the biophysical and spatial properties of voltage-gated Ca2+ channels, leading to enhanced Ca2+ influx into neurons. Specific Aim 2 tests the hypothesis that, α-syn remodels phosphoinositide metabolizing enzymes to increase Ca2+ channel activity. Specific Aim 3 tests the hypothesis that α-syn aberrantly modifies ER and mitochondrial C a2+ signaling nanodomains leading to cytotoxicity. The proposed studies have specific relevance to the fields of neuroscience, cell biology and biophysics, but the fundamental importance of voltage-gated K+ and Ca2+ channels, as well as phosphoinositides mean it will have broad implications for medicine. Findings from this investigation will unveil crucial physiological roles for α-syn in organizing the nanoscale distribution of ion channels in health, as well as revealing novel signaling hubs that can be targeted for the development of therapeutic strategies for PD, ADRD, and synucleinopathies.

项目摘要 α-核蛋白（α-Syn）是由SNCA基因编码的神经元蛋白。从遗传上，SNCA中的突变 基因导致α-突触核蛋白的表达和聚集增强，并引起帕金森氏菌的遗传形式 疾病（PD）。在特发性PD以及阿尔茨海默氏病和相关痴呆症（ADRD）中，α-Syn聚集 导致形成构成Lewy Bodies的基础的有毒α-Syn原纤维，这种变形蛋白 积累并与神经元细胞死亡有关的沉积物。那就是α-syn被认为是关键 PD的病理标志。由于我们不断扩大的预期寿命，估计PD的流行率是 到2030年，年龄是其发展的强大风险因素，目前尚无治愈 已知可以改变疾病进展的治疗性。尽管对α-Syn的神经病理学后果明显 在PD和ADRD中的积累缺乏有关分子的机械细胞内信息 导致细胞死亡的α-syn扰动的途径。此应用的目的是探索这一关键差距 通过检查α-syn是否改变膜接触位点的分子组成来了解。我们的中心 假设是α-syn异常重塑质膜离子通道和脂质以改变内质 网状 - 线粒体Ca2+纳米域导致神经毒性。我们的数据支持PD是 纳米结构疾病。为了检验这一假设，我们实施了创新的多尺度（包括脂质组学， 超级成像，遗传学和斑块钳电生理学）垂直整合信号的方法 从单个脂质到神经元网络的级联，目的是提供基本知识 这将有助于发展新型策略，这些新策略会减慢或减少神经毒性α-Syn介导的细胞死亡。 特定目标1检验了α-Syn重塑电压门控钾和Ca2+纳米复合物的假设 改变电压门控的生物物理和空间特性 CA2+通道，导致CA2+的增强影响到 神经元。具体目标2检验了以下假设：α-Syn将磷酸肌醇代谢酶重塑为 增加CA2+通道活动。特定目标3检验了α-伴侣异常修饰ER的假设，并且 线粒体c A2+信号传导纳米域导致细胞毒性。 拟议的研究具有特定的相关性 到神经科学，细胞生物学和生物物理学领域，但电压门控k+的基本重要性 和Ca2+通道以及磷酸肌醇意味着它将对医学具有广泛的影响。来自 这项投资将在组织离子的纳米级分布中揭示α-syn的关键生理作用 健康渠道，以及揭示可用于开发的新型信号枢纽 PD，ADRD和突触核心病的治疗策略。