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：
8703547
负责人：
Kelly M Lohr
金额：
$ 3.14万
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703547
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 Data Development Disease Disease model Dopamine Dorsal Dose Drug Modulation Economics Environment Epidemiology Etiology Gene Mutation Genetic Genetic Predisposition to Disease Goals Haplotypes 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 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 public health relevance 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）：帕金森氏病（PD）的特征是运动，僵硬和静止震颤的速度减慢，原因是nigra的多巴胺能神经元进行了性变性。尽管在鉴定该疾病的遗传原因方面取得了进展，但遗传突变仅占PD病例的5-10％。因此，我们的实验室有兴趣追求遗传易感性与环境侮辱之间的相互作用。囊泡单胺转运蛋白2（VMAT2）将单胺神经递质隔离到受PD影响的细胞中的囊泡中，从而可以快速突触释放。 VMAT2还提供了保护这些发射机内部和环境有毒物质的破裂影响的保护。我们的实验室先前已经表征了一个小鼠模型，其中VMAT2降低了95％。这些小鼠表现出黑质的多巴胺神经元的进行性细胞死亡，A-核蛋白积累以及PD的运动和非运动症状。由于VMAT2水平或功能可能是介导该疾病易感性的关键，因此升高的VMAT2水平可能在PD中具有治疗益处。我们开发了一种过表达VMAT2的转基因小鼠。这些小鼠的VMAT2和囊泡多巴胺的吸收是野生型小鼠的两倍，并改善了焦虑和抑郁行为的结果。这些初步数据表明，VMAT2-HI小鼠的表型与帕金森氏症抗性的VMAT2-LO小鼠相反。该提案的目的是研究升高VMAT2水平来营救帕金森氏症表型的潜力。这项研究将检查我们小鼠中不同VMAT2水平的病理和行为影响1）急性施用毒物MPTP和2）病毒载体介导的A53T A-核蛋白的过表达。该提案将表明VMAT2水平是否能够降低PD症状的严重程度。拟议研究的完成将揭示VMAT2水平与PD症状的严重程度之间的相互作用，并突出药物调节VMAT2调节的治疗潜力。