Methamphetamine and Parkinson's disease: converging mechanisms of pathogenesis

 描述(由申请人提供)：本K99/R00建议书是为支持、培训Graves博士并将其从指导人员转变为独立研究人员而提交的。该提案的重点是甲基苯丙胺可能增加患帕金森氏症风险的机制。最近的流行病学研究发现，甲基苯丙胺的使用与帕金森病风险增加近2-3倍有关。帕金森氏症患者，向基底节提供多巴胺的黑质致密部神经元逐渐退化。这些神经元的丧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，起搏期间这些神经元中的Cav1.3 L型钙通道活动通过增加线粒体氧化应激而推动变性。初步数据显示，长期服用甲基苯丙胺会加快起搏频率，潜在地导致Cav1.3活性增加和线粒体氧化应激增加。此外，甲基苯丙胺似乎引起多巴胺能神经末梢氧化应激的增加，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所致。多巴胺代谢的升高被认为会导致代谢产物的增加，从而对细胞造成损害，从而增加终末和树突区的氧化应激。该提案的最后一个主题是追问有关冰毒使用会增加帕金森氏症标志的α-突触核蛋白病理的报道。我们假设甲基苯丙胺诱导的应激对于α-突触核蛋白病理学的发展是必要的。因此，我们提出了在小鼠身上进行的四个具体目标。提案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的学术神经学家的职业目标。K99目的I：确定急性甲基苯丙胺是否会增加终末/树突状线粒体应激，而慢性甲基苯丙胺是否会增加活性依赖的躯体树突状线粒体应激。目的II：确定慢性甲基苯丙胺是否会诱发α-突触核蛋白病变。R00目的III：确定甲基苯丙胺诱导的氧化应激是否与单胺氧化酶-B的多巴胺代谢有关。R00目的IV：确定单胺氧化酶-B和Cav1.3钙通道活性是否是α-突触核蛋白聚集所必需的。提案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的学术神经学家的职业目标。

 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.