Methamphetamine and Parkinson's disease: converging mechanisms of pathogenesis

 描述（由申请人提供）：提交本K99/R 00提案，以支持、培训Graves博士，并将其从指导研究者转变为独立研究者。该提案的重点是甲基苯丙胺可能增加患帕金森病风险的机制。最近的流行病学研究发现，甲基苯丙胺的使用与帕金森病的风险增加近2-3倍有关。在帕金森氏病中，黑质神经元（为基底神经节提供多巴胺）进行性退化。这些神经元的缺失是导致这种疾病的主要运动症状的原因。Surmeier实验室发表的研究表明，在起搏过程中，这些神经元中的Cav1.3 L型钙通道活性通过增加线粒体氧化应激来驱动退化。初步数据表明，慢性甲基苯丙胺给药加速起搏频率，可能导致Cav1.3活性增加和线粒体氧化应激升高。此外，甲基苯丙胺似乎引起多巴胺能神经末梢中氧化应激的升高，这是由于单胺氧化酶-B的活性非依赖性单胺释放和多巴胺代谢。假设多巴胺代谢的升高导致代谢物增加，代谢物增加可能对细胞造成损害，从而增加终末和树突区域的氧化应激。该提案的最后一个主题是关于甲基苯丙胺使用增加α-突触核蛋白病理学的报告，这是帕金森病的标志。我们假设甲基苯丙胺诱导的应激是α-突触核蛋白病理学发展所必需的。因此，我们建议在小鼠中进行四个特定目的。建议书中详细介绍的培训计划将扩大和推进格雷夫斯博士成为一名独立学术神经科学家的职业目标。K99目标I：确定急性甲基苯丙胺是否会增加终末/树突状细胞线粒体应激，慢性甲基苯丙胺是否会增加活性依赖性体细胞树突状细胞线粒体应激。K99目的II：确定慢性甲基苯丙胺是否会诱导α-突触核蛋白病理学。目的III：确定甲基苯丙胺诱导的氧化应激是否可归因于单胺氧化酶-B的多巴胺代谢。R 00目的IV：确定单胺氧化酶-B和Cav1.3 Ca 2+通道活性是否是α-突触核蛋白聚集所必需的。建议书中详细介绍的培训计划将扩大和推进格雷夫斯博士成为一名独立学术神经科学家的职业目标。

 DESCRIPTION (provided by applicant): This K99/R00 proposal is submitted for the support, training, and transition of Dr. Graves from a mentored to independent investigator. The proposal is focused on the mechanisms by which methamphetamine might increase the risk of developing Parkinson's disease. Recent epidemiological work has found that methamphetamine use is associated with nearly ~2-3-fold increased risk for Parkinson's disease. In Parkinson's disease, neurons in the substantia nigra pars compacta, which provide dopamine to the basal ganglia, progressively degenerate. The loss of these neurons is responsible for the cardinal motor symptoms of the disease. Published work from the Surmeier lab indicates that Cav1.3 L-type calcium channel activity in these neurons during pacemaking drives degeneration by increasing mitochondrial oxidant stress. Preliminary data indicates that chronic methamphetamine administration accelerates pacemaking frequency, potentially leading to increased Cav1.3 activity and elevated mitochondrial oxidant stress. Additionally, methamphetamine appears to cause elevations in oxidant stress in dopaminergic nerve terminals due to activity-independent monoamine release and dopamine metabolism by monoamine oxidase-B. Elevation in dopamine metabolism is hypothesized to lead to increased metabolites that can be damaging to the cells and thus increase oxidant stress at terminals and dendritic fields. The final topic of the proposal pursues reports that methamphetamine use increases α-synuclein pathology, a hallmark of Parkinson's disease. We hypothesize that methamphetamine- induced stress is necessary for the development of α-synuclein pathology. Accordingly, we propose four Specific Aims to be conducted in mice. The training program detailed in the proposal will expand and advance Dr. Graves' career objective of becoming an independent academic neuroscientist. K99 Aim I: To determine if acute methamphetamine will increase terminal/dendritic mitochondrial stress and chronic methamphetamine will increase activity-dependent somatodendritic mitochondrial stress. K99 Aim II: To determine if chronic methamphetamine will induce α-synuclein pathology. R00 Aim III: To determine if methamphetamine- induced oxidant stress is attributable to dopamine metabolism by monoamine oxidase-B. R00 Aim IV: To determine if monoamine oxidase-B and Cav1.3 Ca2+ channel activity is necessary for α-synuclein aggregation. The training program detailed in the proposal will expand and advance Dr. Graves' career objective of becoming an independent academic neuroscientist.