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

基本信息

批准号：
10040481
负责人：
ZACHARY FREYBERG
金额：
$ 23.48万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10040481
关键词：
Address Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease related dementia Animal Model Animals Candidate Disease Gene Cells Comparative Study Data Data Set Dementia Disease Disease Progression Disease model Dopamine Drosophila genus Exhibits Female Functional disorder Genes Genetic Glutamate Transporter Human Individual Intervention Lead Lewy Bodies Lewy Body Dementia 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 Preventive Intervention 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 resilience response sex stressor synucleinopathy tool transcriptome sequencing

项目摘要

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.

Lewy Bodies（DLB）的痴呆症是第二大常见的痴呆症，继阿尔茨海默氏病之后，患有阿尔茨海默氏病， 65岁及以上的人的患病率显着升高。 DLB中的核心病理是进步的尤其针对中脑多巴胺（DA）的Lewy身体中错误折叠的α-突触核蛋白的病理积累神经元并导致其退化。响应突触核苷的这种神经元丧失是重要的不仅在DLB中，而且在阿尔茨海默氏病中也发现了脆弱性。鉴于跨越共享功能疾病，鉴定DA神经变性的机制响应于突触核酸的疾病可能会提供对与年龄相关的神经退行性共同的神经元脆弱性和韧性的批判性见解疾病。但是，我们仍然对神经元脆弱性的机制和弹力。值得注意的是，我们已经建立了比较果蝇和小鼠的完整方法与年龄有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为影响与年龄相关的神经变性的进化配置的细胞和分子途径提供新的见解。使用这些方法，我们已经确定了囊泡谷氨酸转运蛋白 vglut（哺乳动物中的VGLUT2和果蝇中的dvglut）作为对弹性的新调节剂 DA神经元中的神经变性。实际上，上调vglut表达的DA神经元更具抵抗力包括响应α-核蛋白的病理积累 - 蝇和小鼠中保守的反应。到阐明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套件选择性区分和操纵在苍蝇和小鼠中表达vglut的DA神经元的工具。与这些工具和模型，我们现在可以回答关键问题：1）调节的配置机制是什么 da神经元vglut在突触核酸中的表达？ 2）vglut表达调节器调节器调节器对突触性核酸引起的神经变性的韧性吗？为了解决这个问题，我们利用苍蝇的优势遗传障碍性快速识别脆弱性和韧性的新目标，然后在突触核苷的小鼠模型。我们的中心假设是：i）da神经元VGLUT表达在紧密之下调节性控制和所涉及的基因对于剧明病中的VGLUT上调至关重要（AIM 1）。 ii） vglut表达的上调是一种促生存的应对机制，是调节这一点的基因 DA神经元中VGLUT表达的增加有助于突触核酸的弹性（AIM 2）。使用我们的比较方法，我们可以确定各种物种中保守的新型介入目标以提高 DA神经元中的弹性。这些新目标最终可能会在其他细胞类型中进行测试，以作为更广泛的干预措施为了预防，缓解和治疗DLB，阿尔茨海默氏病和阿尔茨海默氏症的神经变性与疾病有关的痴呆症。