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
基本信息
- 批准号:10582080
- 负责人:
- 金额:$ 47.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AgeAgingAutopsyBiogenesisBiological MarkersBrainCytoplasmDataDisease modelDopamineDoseDrosophila genusEnvironmental MonitoringExposure toFemaleGenesGeneticGenetic TranscriptionGlutamate TransporterGlutathioneHumanImaging DeviceInjuryKnock-outLinkMammalsMediatingMidbrain structureMitochondriaNerve DegenerationNeuronal InjuryNeurotoxinsOrthologous GeneParaquatParkinson DiseasePathway interactionsPatientsPesticidesRattusReactive Oxygen SpeciesRecyclingRegulationRiskRodentRodent ModelRoleRotenoneSex DifferencesSubstantia nigra structureTestingToxic Environmental SubstancesToxicant exposureTranslatingTranslational RegulationVesicleWomanalpha synucleinbrain tissuecohortcomparativedisorder controldopaminergic neuroneffective therapyexposed human populationfemale sex hormoneflyinsightknock-downmalemenmitochondrial metabolismneuron lossneuronal survivalneuroprotectionnoveloverexpressionpesticide exposureresilienceresponsesexsexual dimorphismtoxicanttranscriptome sequencing
项目摘要
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
暴露于包括杀虫剂在内的环境毒物会导致黑质多巴胺(DA)神经元丢失,
黑质(SN),并增加患帕金森病(PD)的风险。毒物暴露研究表明,
二态性DA神经元弹性,使得女性比男性失去更少的DA神经元。这种性别差异是
相关,因为女性PD的患病率较低,症状发作的年龄较晚。但
DA神经元对毒物的恢复力的这些性别差异的机制仍然知之甚少。我们有
利用果蝇和啮齿类动物DA神经变性模型的各自优势,
研究毒物对选择性DA神经元恢复力的影响,
帕金森病患者的组织我们在哺乳动物中鉴定了囊泡谷氨酸转运蛋白VGLUT 2,
果蝇直系同源基因dVGLUT作为DA神经元弹性性别差异的调节剂。我们发现:1)
dVGLUT/VGLUT 2 + DA神经元比不表达dVGLUT/VGLUT 2 + DA神经元更可能在损伤后存活。
2)DA神经元中的条件性dVGLUT/VGLUT 2敲除增加对损伤的脆弱性;以及3)
在存活的DA神经元中,dVGLUT/VGLUT 2表达上调,以响应PD相关损伤,包括
老化、错误折叠的α-突触核蛋白和神经毒素。此外,我们发现女性表达更多
与雄性相比,DA神经元中的dVGLUT/VGLUT 2-这一发现在果蝇、啮齿动物和人类中得到了保留
这可能解释了帕金森病的性别差异。然而,DA神经元VGLUT 2表达的性别差异是否
对环境毒物如鱼藤酮和百草枯的恢复力有何贡献尚不清楚。因此我们
假设DA神经元dVGLUT/VGLUT 2表达是保守的、性二态性神经保护因子的一部分,
对环境毒物损伤DA神经元的反应。为了验证我们的假设,我们开发了
比较方法跨越苍蝇,啮齿动物和死后人脑,沿着随着新的遗传和成像
工具,以确定VGLUT 2是否调节DA神经元对农药鱼藤酮的弹性的性别差异
(Aim 1)。我们还将确定dVGLUT和VGLUT 2介导的对农药的抗性的机制,
男性和女性(目标2)。最后,我们将确定DA神经元VGLUT 2在男性和女性大脑中的表达,
女性帕金森病患者,包括已知接触杀虫剂七氯的受试者的大脑(目标3)。
VGLUT 2在环境毒物致DA神经元恢复力性别差异中的作用
暴露可能为PD提供新的见解。此外,确定DA能神经元增加的机制,
女性的韧性可以转移到男性,以提高PD中DA神经元的存活率。这可能最终导致
新的,有效的治疗方法,以减缓或停止PD神经变性的男性和女性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ZACHARY FREYBERG其他文献
ZACHARY FREYBERG的其他文献
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{{ truncateString('ZACHARY FREYBERG', 18)}}的其他基金
Request for a ThermoFisher Helios 5UC DualBeam
索取 ThermoFisher Helios 5UC DualBeam
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10719755 - 财政年份:2023
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胰岛激素分泌和抗精神病药物引起的代谢紊乱的新多巴胺能机制
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10453448 - 财政年份:2021
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Novel dopaminergic mechanisms of islet hormone secretion and antipsychotic drug-induced metabolic disturbances
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Novel dopaminergic mechanisms of islet hormone secretion and antipsychotic drug-induced metabolic disturbances
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