Novel roles of VGLUT in sex differences in dopamine neuron vulnerability to environmental toxicant-induced neurodegeneration

VGLUT 在多巴胺神经元易受环境毒物诱导的神经变性的性别差异中的新作用

• 批准号: 10582080
• 负责人: ZACHARY FREYBERG
• 金额: $ 47.43万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-06 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582080
• 关键词: Age; Aging; Autopsy; Biogenesis; Biological Markers; Brain; Cytoplasm; Data; Disease model; Dopamine; Dose; Drosophila genus; Environmental Monitoring; Exposure to; Female; Genes; Genetic; Genetic Transcription; Glutamate Transporter; Glutathione; Human; Imaging Device; Injury; Knock-out; Link; Mammals; Mediating; Midbrain structure; Mitochondria; Nerve Degeneration; Neuronal Injury; Neurotoxins; Orthologous Gene; Paraquat; Parkinson Disease; Pathway interactions; Patients; Pesticides; Rattus; Reactive Oxygen Species; Recycling; Regulation; Risk; Rodent; Rodent Model; Role; Rotenone; Sex Differences; Substantia nigra structure; Testing; Toxic Environmental Substances; Toxicant exposure; Translating; Translational Regulation; Vesicle; Woman; alpha synuclein; brain tissue; cohort; comparative; disorder control; dopaminergic neuron; effective therapy; exposed human population; female sex hormone; fly; insight; knock-down; male; men; mitochondrial metabolism; neuron loss; neuronal survival; neuroprotection; novel; overexpression; pesticide exposure; resilience; response; sex; sexual dimorphism; toxicant; transcriptome sequencing

PROJECT SUMMARY Exposure to environmental toxicants including pesticides causes dopamine (DA) neuron loss in the substantia nigra (SN) and raises risk for developing Parkinson’s disease (PD). Toxicant exposure studies show sexually dimorphic DA neuron resilience, such that females lose fewer DA neurons than males. This sex difference is relevant since PD in women is less prevalent and has a later age of symptomatic onset. However, the mechanisms for these sex differences in DA neuron resilience to toxicants remain poorly understood. We have leveraged the respective advantages of fly and rodent models of DA neurodegeneration to provide new insights into toxicants’ effects on selective DA neuron resilience, which we have translated to human postmortem brain tissue from PD patients. We identified the vesicular glutamate transporter VGLUT2 in mammals and its Drosophila ortholog dVGLUT as modulators of sex differences in DA neuron resilience. We find: 1) dVGLUT/VGLUT2+ DA neurons are likelier to survive insults versus DA neurons that do not express the transporter; 2) Conditional dVGLUT/VGLUT2 knockout in DA neurons increases vulnerability to insults; and 3) dVGLUT/VGLUT2 expression is upregulated in surviving DA neurons in response to PD-linked insults including aging, misfolded a-synuclein, and neurotoxins. Furthermore, we discovered females express more dVGLUT/VGLUT2 in DA neurons compared to males – a finding conserved across flies, rodents and humans that may explain the sex differences in PD. Yet, whether sex differences in DA neuron VGLUT2 expression contribute to resilience to environmental toxicants like rotenone and paraquat remains unknown. Thus, we hypothesize DA neuron dVGLUT/VGLUT2 expression is part of a conserved, sexually dimorphic neuroprotective response to DA neuron injury by environmental toxicants in PD. To test our hypothesis, we developed comparative approaches across flies, rodents and postmortem human brain, along with new genetic and imaging tools, to determine whether VGLUT2 modulates sex differences in DA neuron resilience to the pesticide rotenone (Aim 1). We will also determine the mechanisms for dVGLUT- and VGLUT2-mediated resilience to pesticides in males and females (Aim 2). Lastly, we will determine DA neuron VGLUT2 expression in brains of male and female PD patients, including in brains of subjects with known exposure to the pesticide heptachlor (Aim 3). Identifying VGLUT2’s roles in sex differences in DA neuron resilience as a result of environmental toxicant exposure may provide new insights into PD. Moreover, determining the mechanisms of increased DA neuron resilience in females can be transferred to males to boost DA neuron survival in PD. This may ultimately lead to new, effective treatments to either slow or stop PD neurodegeneration in both men and women.

项目摘要 暴露于包括农药在内的环境有毒物质会导致多巴胺（DA）神经元丧失 Nigra（SN）和发展帕金森氏病的风险（PD）。 二态DA神经元的弹性，使女性失去的DA神经元比男性少。 相关性，因为女性的PD较少，并且具有症状发作的年龄。 DA神经元中这些性别差异的机制对毒性的理解仍然很差。 利用了DA神经变性的苍蝇和啮齿动物模型的尊敬优势，以提供新的见解 进入有毒物质对选择性DA神经元的弹性的影响，我们已将其转化为人类后大脑 来自PD患者的组织。 果蝇直齿DVGLUT作为DA神经元的性别差异的调节剂。 dvglut/vglut2+ da神经元更有可能生存，而不是表达不表达的da神经元 Transporter; 2）DA神经元中的有条件DVGLUT/VGLUT2敲除 dvglut/vglut2表达在幸存的DA神经元中被置于PD连接，包括 衰老，不折叠的A核蛋白和神经毒素。 与雄性相比 这可能解释了PD中的性别差异。 有弹性的有毒物质，例如烤面包酮和帕拉酮，因此，我们是未知的 假设的DA Neuron dvglut/vglut2表达是保守的性二型神经保护性的一部分 在PD中对环境有毒物质的DA神经元损伤的反应。 跨苍蝇，啮齿动物和尸体后人脑的比较方法，以及新的遗传和成像 工具，确定vglut2是否在da神经元中对农药藤酮的弹性中的性别差异化 （AIM 1）。 男性和女性（AIM 2）。 女性PD患者，无知的受试者大脑已知暴露于农药七氯（AIM 3）。 识别vglut2在DA神经元弹性中的性别差异中的作用，如环境毒物的艺术 暴露可能会提供新的见解，以确定增加DA神经元的机制 女性的韧性可以转移到男性中，以提高DA神经元的生存。 在男性和女性中，新的有效治疗方法可以缓慢或停止PD神经退行性。