VMAT2-mediated rescue of Parkinsons disease pathology and behavior

VMAT2 介导的帕金森病病理和行为的挽救

基本信息

批准号：
8896082
负责人：
Kelly M Lohr
金额：
$ 1.07万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8896082
关键词：
1-Methyl-4-phenylpyridinium Accounting Acute Affect American Animal Model Anxiety Attenuated Behavior Behavioral Brain region Caring Cell Death Cells Cessation of life Corpus striatum structure DNA Sequence Alteration Data Development Disease Disease model Dopamine Dorsal Dose Drug Modulation Economics Environment Epidemiology Etiology Genetic Genetic Predisposition to Disease Goals Haplotypes Health High Pressure Liquid Chromatography Immunoblotting Immunohistochemistry Intervention Knowledge Length Link Locomotion Measures Mediating Metabolism Mitochondria Modeling Motor Motor Activity Movement Mus Neurons Neurotransmitters Outcome Oxidative Stress Parkinson Disease Parkinsonian Disorders Pathology Patients Phenotype Positioning Attribute Predisposition Proteins Public Health Recombinant adeno-associated virus (rAAV)Resistance Rest Tremor Severities Site Substantia nigra structure Symptoms Synapses Synaptic Transmission Techniques Testing Therapeutic Toxic Environmental Substances Toxic effect Transgenic Animals Transgenic Mice Variant Vesicle Viral Vector adeno-associated viral vector aging population alpha synuclein attenuation behavior test depressive behavior depressive symptoms dopaminergic neuron experience extracellular gain of function improved insight interest monoamine mouse model mutant neuronal cell body new therapeutic target non-motor symptom novel overexpression oxidation pars compacta prevent response synuclein toxicant uptake vesicular monoamine transporter 2

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is characterized by slowed movement, rigidity, and resting tremors resulting from progressive degeneration of dopaminergic neurons in the substantia nigra. Though there has been progress in identifying genetic causes of this disease, genetic mutations only account for 5-10% of PD cases. Thus, our lab is interested in pursuing the interaction between genetic susceptibility and environmental insults. The vesicular monoamine transporter 2 (VMAT2) sequesters monoamine neurotransmitters into vesicles in cells affected by PD, allowing for rapid synaptic release. VMAT2 also provides protection from the effects of the breakdown of these transmitters inside the cell and from environmental toxicants. Our lab has previously characterized a mouse model with a 95% reduction in VMAT2. These mice show progressive cell death of the dopamine neurons of the substantia nigra, a-synuclein accumulation, and both motor and non-motor symptoms of PD. As VMAT2 levels or function may be key in mediating susceptibility to this disease, it is possible that increased VMAT2 levels could have therapeutic benefit in PD. We have developed a transgenic mouse that overexpresses VMAT2. These mice have twice as much VMAT2 and vesicular dopamine uptake as wildtype mice and improved outcomes on measures of anxiety and depressive behavior. These preliminary data suggest that the VMAT2-HI mice show a phenotype opposite of the VMAT2-LO mice with resistance to the parkinsonian state. The goal of this proposal is to examine the potential for elevated VMAT2 levels to rescue parkinsonian phenotypes. This study will examine the pathological and behavioral effects of varying VMAT2 levels in our mice following 1) an acute administration of the toxicant MPTP and 2) viral vector- mediated overexpression of A53T a-synuclein. This proposal will show if increased VMAT2 levels are able to decrease the severity of PD symptoms. Completion of the proposed studies will reveal interaction between VMAT2 level and severity of PD symptoms and highlight the therapeutic potential of VMAT2 modulation by drugs.

描述（由申请人提供）：帕金森病（PD）的特征是由于黑质中的多巴胺能神经元进行性变性而导致的运动减慢、僵硬和静止性震颤。尽管在确定这种疾病的遗传原因方面取得了进展，但基因突变仅占 PD 病例的 5-10%。因此，我们的实验室有兴趣研究遗传易感性和环境侵害之间的相互作用。囊泡单胺转运蛋白 2 (VMAT2) 将单胺神经递质隔离到受 PD 影响的细胞的囊泡中，从而实现突触的快速释放。 VMAT2 还可以提供保护，免受细胞内这些递质分解的影响以及环境毒物的影响。我们的实验室之前已经鉴定出 VMAT2 降低 95% 的小鼠模型。这些小鼠表现出黑质多巴胺神经元进行性细胞死亡、α-突触核蛋白积累以及帕金森病的运动和非运动症状。由于 VMAT2 水平或功能可能是介导对该疾病易感性的关键，因此增加 VMAT2 水平可能对 PD 具有治疗益处。我们开发了一种过度表达 VMAT2 的转基因小鼠。这些小鼠的 VMAT2 和囊泡多巴胺摄取量是野生型小鼠的两倍，焦虑和抑郁行为的测量结果也有所改善。这些初步数据表明，VMAT2-HI 小鼠表现出与 VMAT2-LO 小鼠相反的表型，对帕金森病状态具有抵抗力。该提案的目标是检查提高 VMAT2 水平挽救帕金森表型的潜力。本研究将检查小鼠中不同 VMAT2 水平的病理和行为影响，如下：1）急性施用有毒物质 MPTP 和 2）病毒载体介导的 A53T α-突触核蛋白过度表达。该提案将表明增加 VMAT2 水平是否能够减轻 PD 症状的严重程度。拟议研究的完成将揭示 VMAT2 水平与 PD 症状严重程度之间的相互作用，并强调药物调节 VMAT2 的治疗潜力。