Novel Molecular Genetic Approaches for the Prevention and Treatment of Parkinsons

描述(申请人提供)：帕金森病(PD)是一种由中脑多巴胺神经元变性引起的运动障碍。然而，在帕金森病和帕金森病动物模型中，这些细胞的一个亚群相对较少。帕金森病动物模型是从腹侧被盖区(VTA)投射到腹内侧纹状体(VMS或伏隔核内侧壳)的动物模型。这个投射还包含许多多巴胺神经元，它们表达囊泡性谷氨酸转运体(VGLUT2)并共同释放兴奋性神经递质谷氨酸。由于VGLUT2和囊泡单胺转运体(VMAT2)似乎定位于VMS中重叠的突触小泡群体，谷氨酸的囊泡共同进入可能通过增加囊泡pH梯度(DPH)来提供神经保护。预计较大的DPH会增加多巴胺的囊泡存储，将多巴胺和其他潜在的细胞毒性VMAT2底物隔离到囊体中，从而减轻它们的毒性。这项提案的第一个目的将使用选择性条件基因敲除小鼠和病毒表达策略来测试VGLUT2是否在PD的MPTP损伤模型中提供神经保护益处。帕金森病或帕金森病模型中的多巴胺神经元丢失后，基底节中的多巴胺感受性中间体棘神经元(MSN)的输出受到失调。特别是，间接通路中含有MSN的多巴胺D2受体的过度激活，以及随之而来的丘脑底核的过度兴奋，似乎是与PD相关的最严重的运动症状的原因。因此，我们将测试间接通路输出的极性从抑制到兴奋是否可以恢复帕金森病损伤模型中的运动行为。这些研究将检验新的假说和神经回路中一个新的分子靶点(VGLUT2)，这些分子与帕金森病有关。这项工作将提供有关这些回路对兴奋性递质释放变化的可塑性的重要信息，并可能为帕金森病的治疗和预防提供新的途径。

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a motor disorder brought on by neurodegeneration of midbrain dopamine neurons. However, a subpopulation of these cells is relatively spared both in PD and in PD animal models - those that project from the medial ventral tegmental area (VTA) to the ventromedial striatum (VMS or the medial shell of the nucleus accumbens). This projection also contains many dopamine neurons that express the vesicular glutamate transporter (VGLUT2) and co-release the excitatory neurotransmitter glutamate. Because VGLUT2 and the vesicular monoamine transporter (VMAT2) appear to localize to an overlapping population of synaptic vesicles in the VMS, the vesicular co-entry of glutamate may confer neuroprotection by increasing the vesicular pH gradient (DpH). Larger DpH would then be predicted to increase the vesicular storage of dopamine, serving to sequester dopamine and other potentially cytotoxic VMAT2 substrates into vesicular bodies where their toxicity is mitigated. The first aim of this proposal will test whether VGLUT2 confers neuroprotective benefits in an MPTP lesion model of PD using selective conditional knockout mice and viral expression strategies. Following the loss of dopamine neurons in PD or PD lesion models, output from the dopaminoceptive medium spiny neurons (MSN) in the basal ganglia is dysregulated. In particular, over-activation of the dopamine D2 receptor containing MSNs of the indirect pathway and consequent over-excitation of the subthalamic nucleus appear to account for the most severe motor symptoms associated with PD. We will thus test whether flipping the polarity of indirect pathway output from inhibitory to excitatory can restore motor behaviors in a PD lesion model. These studies will test novel hypotheses and a new molecular target (VGLUT2) in the neural circuitry that contribute to PD. The work will provide important information about the plasticity of these circuits to changes in excitatory transmitter release, an may lead to new approaches for the treatment and prevention of Parkinson's Disease.