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.

项目概要 α-突触核蛋白 (α-syn) 是一种由 SNCA 基因编码的神经元蛋白，在遗传上是 SNCA 的突变。 基因导致 α-突触核蛋白的表达和聚集增强，并导致遗传性帕金森病 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。 导致有毒 α-syn 原纤维的形成，这些原纤维构成了路易体（异常蛋白）的组成部分 积累并与神经细胞死亡相关的沉积物因此，α-syn 被认为是关键。 PD 的病理特征 由于我们的预期寿命不断延长，PD 的患病率估计为 到 2030 年将翻一番。年龄是其发展的最强风险因素，目前尚无治愈方法，也没有 尽管 α-syn 具有明显的神经病理学后果，但已知治疗可以改变疾病进展。 PD 和 ADRD 中的积累缺乏有关分子的细胞内机制信息 α-syn 扰动导致细胞死亡的途径本应用的目标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获得知识。 假设是 α-syn 异常地重塑质膜离子通道和脂质，从而改变内质 网状结构——线粒体 Ca2+ 纳米结构域导致神经毒性。我们的数据支持 PD 是这样的概念。 为了检验这一假设，我们实施了一种创新的多尺度（包括脂质组学， 超分辨率成像、遗传学和膜片钳电生理学）垂直整合信号传导的方法 从单一脂质水平级联到神经网络，目标是提供基础知识 这将有助于开发减缓或减少神经毒性α-syn介导的细胞死亡的新策略。 具体目标 1 检验 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+ 流入增强 具体目标 2 检验以下假设：α-syn 将磷酸肌醇代谢酶重塑为 增加 Ca2+ 通道活性 3 测试了 α-syn 异常改变 ER 和 线粒体C a2+ 信号传导纳米结构域导致细胞毒性。 拟议的研究具有特定的相关性 对于神经科学、细胞生物学和生物物理学领域来说，电压门控 K+ 的根本重要性 和 Ca2+ 通道以及磷酸肌醇意味着它将对医学产生广泛的影响。 这项研究将揭示 α-syn 在组织离子纳米级分布中的重要生理作用 健康渠道，以及揭示可针对发展的新型信号中心 PD、ADRD 和突触核蛋白病的治疗策略。