Mechanisms for Preserving Neurons in Alzheimer's Disease-Related Dementias Across Drosophila and Mouse Models

果蝇和小鼠模型中阿尔茨海默病相关痴呆的神经元保护机制

• 批准号: 10264846
• 负责人: ZACHARY FREYBERG
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264846
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Animal Model; Animals; Candidate Disease Gene; Cells; Comparative Study; Data; Data Set; Dementia; Dementia with Lewy Bodies; Disease; Disease Progression; Disease model; Dopamine; Drosophila genus; Exhibits; Female; Functional disorder; Genes; Genetic; Glutamate Transporter; Human; Individual; Intervention; Lead; Lewy Bodies; Lewy body pathology; Mammals; Midbrain structure; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; Orthologous Gene; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Phenotype; Prevalence; Prevention therapy; RNA interference screen; Role; Sex Differences; Source; Testing; Up-Regulation; Work; age related neurodegeneration; aged; alpha synuclein; associated symptom; cell type; comparative; coping mechanism; dopaminergic neuron; fly; innovation; insight; knock-down; motor symptom; mouse model; neuron loss; neuropsychiatric symptom; novel; novel therapeutics; preservation; preventive intervention; resilience; response; sex; stressor; synucleinopathy; tool; transcriptome sequencing

Dementia with Lewy bodies (DLB) is the second most common dementia, following Alzheimer’s disease, with prevalence rising significantly in people aged 65 years and older. The core pathology in DLB is progressive pathologic accumulation of misfolded α-synuclein in Lewy bodies that especially targets midbrain dopamine (DA) neurons and leads to their degeneration. This neuronal loss in response to synucleinopathy is an important source of vulnerability not only in DLB, but is also found in Alzheimer’s disease. Given the shared features across disorders, identifying mechanisms of DA neurodegeneration in response to synucleinopathy may provide critical insights into neuron vulnerability and resilience common to age-related neurodegenerative disorders. However, we still lack basic understanding of the mechanisms underlying neuronal vulnerability and resilience. Significantly, we have established complementary approaches comparing Drosophila and mouse models of age-related neurodegenerative disease. We exploit the similarities and differences between the two species to provide novel insights into evolutionarily conserved cellular and molecular pathways that affect age-related neurodegeneration. Using these approaches, we have identified the vesicular glutamate transporter VGLUT (VGLUT2 in mammals and dVGLUT in Drosophila) as a new modulator of resilience to neurodegeneration in DA neurons. Indeed, DA neurons that upregulate VGLUT expression are more resilient including in response to pathologic accumulation of α-synuclein – a conserved response in flies and mice. To elucidate VGLUT’s roles in DA neuron vulnerability, we established an innovative suite of intersectional genetic tools to selectively distinguish and manipulate DA neurons that express VGLUT in flies and mice. With these tools and models, we can now answer key questions: 1) what are the conserved mechanisms regulating expression of DA neuron VGLUT in synucleinopathy? and 2) do regulators of VGLUT expression modulate resilience to neurodegeneration caused by synucleinopathy? To address this, we take advantage of the fly’s genetic tractability to rapidly identify new targets of vulnerability and resilience and then test these candidates in mouse models of synucleinopathy. Our central hypotheses are: i) DA neuron VGLUT expression is under tight regulatory control and the genes involved are critical for VGLUT upregulation in synucleinopathy (Aim 1). ii) Upregulation of VGLUT expression is a pro-survival coping mechanism and the genes that modulate this increased VGLUT expression in DA neurons contribute to resilience in synucleinopathy (Aim 2). Using our comparative approaches, we may identify novel interventional targets conserved across species to boost resilience in DA neurons. These new targets may ultimately be tested in other cell types as a broader intervention for prevention, mitigation and treatment of neurodegeneration in DLB, Alzheimer’s disease and Alzheimer’s disease-related dementias.

路易体痴呆（DLB）是继阿尔茨海默病之后的第二种最常见的痴呆， 65岁及以上人群的患病率显著上升。DLB的核心病理是进行性的 路易体中错误折叠的α-突触核蛋白的病理性积聚，特别是针对中脑多巴胺（DA） 神经元并导致其退化。突触核蛋白病引起的神经元丢失是一个重要的 不仅在DLB中，而且在阿尔茨海默病中也发现了脆弱性的来源。考虑到跨 疾病，识别突触核蛋白病引起的DA神经变性机制可能提供 对与年龄相关的神经退行性疾病常见的神经元脆弱性和恢复力的重要见解 紊乱然而，我们仍然缺乏对神经元脆弱性机制的基本了解， resilience.值得注意的是，我们已经建立了互补的方法比较果蝇和小鼠 与年龄相关的神经退行性疾病的模型。我们利用两者之间的相似性和差异 物种提供新的见解进化保守的细胞和分子途径，影响年龄相关的神经变性。利用这些方法，我们已经确定了囊泡谷氨酸转运蛋白 VGLUT（哺乳动物中的VGLUT 2和果蝇中的dVGLUT）作为一种新的适应性调节剂， DA神经元的神经变性。事实上，上调VGLUT表达的DA神经元更有弹性， 包括对α-突触核蛋白的病理积累的反应--这是苍蝇和小鼠中的保守反应。到 为了阐明VGLUT在DA神经元脆弱性中的作用，我们建立了一套创新的交叉遗传学模型， 有选择地区分和操纵果蝇和小鼠中表达VGLUT的DA神经元。与这些 工具和模型，我们现在可以回答关键问题：1）什么是保守的机制调节 突触核蛋白病中DA能神经元VGLUT的表达以及2）VGLUT表达的调节因子是否调节 对突触核蛋白病引起的神经变性的适应能力为了解决这个问题，我们利用苍蝇的 基因的易处理性，以快速识别脆弱性和弹性的新目标，然后测试这些候选人， 突触核蛋白病的小鼠模型。我们的中心假设是：i）DA神经元VGLUT表达受到严格限制， 调节控制和相关基因对于突触核蛋白病中的VGLUT上调至关重要（Aim 1）。ii）第二阶段 VGLUT表达的上调是一种促生存的应对机制，调节这种机制的基因 DA神经元中增加的VGLUT表达有助于突触核蛋白病的恢复（Aim 2）。使用我们 通过比较方法，我们可以确定跨物种保守的新的干预靶点， DA神经元的弹性这些新靶点最终可能会在其他细胞类型中进行测试，作为更广泛的干预措施 用于预防、减轻和治疗DLB、阿尔茨海默病和阿尔茨海默病中的神经变性， 与疾病有关的痴呆