Vesicular modulation of dopamine neuron toxicity

摘要 米勒实验室已经对神经元中多巴胺的发散性质进行了两年多的研究。 几十年。多巴胺是一种基本的神经递质/神经调节剂，但同时它代表着一种 潜在的内源性毒性来源。我们实验室和其他实验室的数据清楚地表明， 储存不当的多巴胺，通过改变囊泡单胺转运体(VMAT2)的功能，可以诱导 进行性黑质纹状体多巴胺神经变性，与特发性帕金森病惊人地相似。 因此，多巴胺的合成、包装和降解(即内稳态)受到严格控制，以最大限度地减少 潜在的毒性。在之前的资助期间，实验室提供了第一个证据表明突触 囊泡糖蛋白2C(SV2C)是囊泡多巴胺稳态的关键调节因子。我们证明了这一点 SV2C调节突触多巴胺的释放及其在帕金森病脑中的表达变化 组织。2020年4月，另一家实验室确定了SV2C在大型帕金森病患者中的坚定定位 这种蛋白质在帕金森氏病的发病机制中起着关键作用。来自我们实验室的新的初步数据 表明SV2C具有对MPTP的抗性，并能阻止多巴胺从囊泡中渗出。 这些数据作为我们假设的基础，SV2C通过其在突触内保留多巴胺的能力 囊泡，对多巴胺神经毒性具有抵抗力。我们将通过以下具体实例来检验这一假设 目的：目的1，研究SV2C调节囊泡多巴胺稳态的机制。 调节毒物引起的神经毒性。目标2，确定是否引入进化先进的 Sv2蛋白进入模式生物线虫可以提供保护，以防多巴胺能毒性。目标3，至 测定SV2C在小鼠体内的功能特性。目的4，确定SV2C在帕金森病相关疾病中的作用 小鼠的致病机制(基于突触核蛋白和毒物诱导)。完成上述具体目标将提供 关于SV2C在多巴胺神经元功能中的作用，对可疑化学物质的易感性的关键信息 帕金森氏病的发展及其作为治疗干预目标的潜力。

Abstract The Miller laboratory has been conducting research on the divergent nature of dopamine in neurons for over two decades. Dopamine is an essential neurotransmitter/neuromodulator, but at the same time it represents a potential source of endogenous toxicity. Data from our laboratory and others have clearly demonstrated that improperly stored dopamine, via altered function of the vesicular monoamine transporter (VMAT2) can induce progressive nigrostriatal dopamine neurodegeneration that is strikingly similar to idiopathic Parkinson’s disease. The synthesis, packaging, and degradation of dopamine (i.e. homeostasis) is thus tightly regulated to minimize the potential for toxicity. In the previous funding period, the laboratory provided the first evidence that the synaptic vesicle glycoprotein 2C (SV2C) was a key modulator of vesicular dopamine homeostasis. We demonstrated that SV2C regulates synaptic dopamine release and its expression is altered in human Parkinson’s disease brain tissue. In April, 2020 another laboratory identified SV2C in a large Parkinson’s disease GWAS firmly positioning the protein as a key player in Parkinson’s disease pathogenesis. New preliminary data from our laboratory indicate that SV2C can confer resistance to MPTP and that it prevents leakage of dopamine from the vesicle. These data serve as the basis of our hypothesis that SV2C, through its ability to retain dopamine within synaptic vesicles, confers resistance to dopamine neurotoxicity. We will test this hypothesis through the following specific aims: Aim 1, to examine the mechanisms by which SV2C regulates vesicular dopamine homeostasis and mediates toxicant-induced neurotoxicity. Aim 2, to determine whether introducing the evolutionarily advanced SV2 proteins into the model organism C. elegans can confer protection against dopaminergic toxicity. Aim 3, to determine the functional properties of SV2C in mice. Aim 4, to determine the role of SV2C in PD-related pathogenesis (synuclein-based and toxicant-induced) in mice. Completion of the above specific aims will provide critical information on the role of SV2C in dopamine neuron function, vulnerability to chemicals suspected in the development of Parkinson’s disease, and its potential as a target of therapeutic intervention.