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.

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