Alpha-synuclein driven cellular changes and vocal dysfunction in Parkinson's Disease

帕金森病中α-突触核蛋白驱动的细胞变化和发声功能障碍

• 批准号: 10283440
• 负责人: Julie Elizabeth Miller
• 金额: $ 41.55万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283440
• 关键词: Action Potentials; Address; Affect; Animal Model; Appearance; Area; Automobile Driving; Basal Ganglia; Behavior; Behavior Therapy; Behavioral; Biological Models; Birds; Brain; Cell Nucleus; Cell physiology; Cells; Clinical Trials; Closure by clamp; Code; Collection; Corpus striatum structure; Data; Dependovirus; Diagnosis; Disease; Disease Progression; Dopamine; Electrodes; Evaluation; FYN gene; Face; Finches; Foundations; Functional disorder; Future; Genes; Genetic; Globus Pallidus; Glutamates; Goals; Human; Immunohistochemistry; Impairment; Implant; Individual; Knowledge; Laboratories; Limb structure; Literature; Loudness; Measurement; Mediating; Membrane; Modeling; Modification; Motor; Motor output; Mus; Neurons; Neurotransmitters; Output; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pattern; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Procedures; Production; Property; Proteins; Publishing; Rattus; Rodent; Rodent Model; Role; SNCA gene; Sampling; Slice; Structure; Symptoms; Synapses; System; Testing; Thalamic structure; Time; Toxic effect; Tremor; Variant; Viral; Virus; Widespread Disease; Width; alpha synuclein; awake; base; brain electrical activity; cell type; density; early detection biomarkers; experimental study; extracellular; human disease; human subject; in vivo; innovation; motor deficit; motor symptom; neuropathology; neurotransmitter release; overexpression; postsynaptic; pre-clinical; preclinical study; relating to nervous system; targeted treatment; therapeutic development; therapeutic target; therapeutically effective; voltage; voltage clamp; zebra finch

SUMMARY Diagnosis of Parkinson’s Disease (PD) is made late, delaying treatment and limiting the ability to halt disease progression. Treatments that target the prodromal phase of PD, prior to the appearance of the cardinal motor signs (tremor, rigidity, etc) and the degeneration of dopamine-producing neurons, do not exist because we lack reliable biomarkers of early disease. Based on accumulating evidence, vocal dysfunction is present during the prodromal phase of PD and offers a convenient entry point to identify early neuropathological changes as potential treatment targets. Data from our laboratory and others has shown that the overexpression of a known human-PD causing gene, alpha-synuclein (α-syn, SNCA) in the rodent and finch brain, leads to early vocal abnormalities consistent with human disease. As a synaptic protein, α-syn is critically involved in cell functions including facilitating neurotransmitter release. Its cellular toxicity in PD has been targeted in human clinical trials but late in the disease, when the neuropathology is already widespread. In fact, little is known about how the physiological role of α-syn shifts to a pathophysiological one early on in PD. This R21 proposal addresses these shortcomings by investigating early stage abnormalities in vocal motor output that can occur years before traditional motor symptoms. We propose to develop an integrated, early stage platform for the evaluation of the α-syn-mediated changes in neuronal and synaptic activity that drive abnormal vocal output. To do so, we use the zebra finch model system because it has specialized song-dedicated brain nuclei that can be experimentally targeted; cell-specific changes in activity are then directly related to the vocal output. Area X is a song-dedicated nucleus within the finch basal ganglia. Within Area X, striatal Medium Spiny Neurons (MSNs) and Globus Pallidus-like (PAL) projection neurons show singing-related firing activity that is directly related to variations in song structure. When α-syn is virally overexpressed in Area X, we detect PD-like changes in song including reduced pitch, amplitude, and abnormal timing. In Aim 1, we test the hypothesis that these song changes result from reduced MSN activity and increased PAL activity in freely behaving birds implanted with extracellular electrode arrays. Aim 2 tests the hypothesis that α-syn overexpression in Area X results in a time-dependent suppression of glutamatergic currents in MSNs and enhanced GABAergic currents in PAL neurons in living brain slices. Our powerful integrative approach uses in vivo and ex vivo measurements of neural activity to evaluate how α-syn driven changes in specific neuronal sub-types correlates to the behavioral output. The characterization of neuropathophysiological mechanisms underlying early stage PD-like vocal deficits will offer new disease-modifying treatment targets.

概括 帕金森病 (PD) 的诊断较晚，从而延误了治疗并限制了阻止疾病的能力 进展。针对 PD 前驱期（主要运动出现之前）的治疗 体征（震颤、僵硬等）和产​​生多巴胺的神经元的退化并不存在，因为我们缺乏 早期疾病的可靠生物标志物。根据越来越多的证据，发声功能障碍在 PD 的前驱期，并提供了一个方便的切入点来识别早期神经病理学变化： 潜在的治疗目标。我们实验室和其他实验室的数据表明，一种已知的过度表达 啮齿动物和雀类大脑中的人类 PD 致病基因 α-突触核蛋白 (α-syn, SNCA) 会导致早期发声 与人类疾病一致的异常。作为一种突触蛋白，α-syn 与细胞功能密切相关 包括促进神经递质释放。其对帕金森病的细胞毒性已在人体临床试验中确定 但在疾病晚期，神经病理学已经广泛存在。事实上，人们对如何 在 PD 早期，α-syn 的生理作用转变为病理生理作用。此 R21 提案解决了这些问题 通过调查几年前可能发生的发声运动输出的早期异常来弥补缺陷 传统的运动症状。我们建议开发一个综合的早期平台来评估 α-syn 介导的神经元和突触活动变化导致异常的声音输出。为此，我们使用 斑胸草雀模型系统，因为它具有专门用于歌曲的脑核，可以进行实验 有针对性；细胞特异性的活动变化与声音输出直接相关。 Area X 是一首歌曲专用的 雀基底神经节内的核。 X 区内，纹状体中棘神经元 (MSN) 和球状神经元 苍白球样（PAL）投射神经元表现出与歌唱相关的放电活动，该活动与 歌曲结构。当 α-syn 在 X 区病毒性过度表达时，我们检测到歌曲中类似 PD 的变化，包括 降低音调、幅度和异常时序。在目标 1 中，我们测试了这些歌曲变化导致的假设 植入细胞外的自由行为鸟类的 MSN 活性降低和 PAL 活性增加 电极阵列。目标 2 检验 X 区 α-syn 过度表达导致时间依赖性的假设 抑制活体大脑中 MSN 中的谷氨酸能电流并增强 PAL 神经元中的 GABA 能电流 切片。我们强大的综合方法使用神经活动的体内和离体测量来评估 α-syn 如何驱动特定神经元亚型的变化与行为输出相关。这 早期 PD 样声音缺陷背后的神经病理生理学机制的表征将提供 新的疾病缓解治疗目标。