VMAT2-mediated rescue of Parkinsons disease pathology and behavior

描述（由申请人提供）：帕金森病（PD）的特征是黑质多巴胺能神经元进行性变性导致的运动减慢、僵硬和静息震颤。虽然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追求遗传易感性和环境损伤之间的相互作用。囊泡单胺转运体2（VMAT 2）将单胺神经递质隔离到受PD影响的细胞中的囊泡中，从而允许快速突触释放。VMAT 2还提供保护，使其免受细胞内这些递质的破坏和环境毒物的影响。我们的实验室先前已经表征了VMAT 2减少95%的小鼠模型。这些小鼠显示出黑质多巴胺神经元的进行性细胞死亡、α-突触核蛋白积累以及PD的运动和非运动症状。由于VMAT 2水平或功能可能是介导对这种疾病的易感性的关键，因此增加VMAT 2水平可能在PD中具有治疗益处。我们已经开发了过表达VMAT 2的转基因小鼠。这些小鼠的VMAT 2和囊泡多巴胺摄取量是野生型小鼠的两倍，并且改善了焦虑和抑郁行为的测量结果。这些初步数据表明，VMAT 2-HI小鼠显示出与VMAT 2-LO小鼠相反的表型，具有对帕金森病状态的抗性。该提案的目标是检查VMAT 2水平升高以挽救帕金森病表型的潜力。本研究将检查在1）急性施用毒物MPTP和2）病毒载体介导的A53 T α-突触核蛋白过表达后，我们的小鼠中不同VMAT 2水平的病理和行为影响。该提案将显示VMAT 2水平的增加是否能够降低PD症状的严重程度。完成拟议的研究将揭示VMAT 2水平与PD症状严重程度之间的相互作用，并突出药物调节VMAT 2的治疗潜力。

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.