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上升。尤其针对中脑蛋白多巴胺（DA）的Lewy身体中错误折叠的α-核蛋白的病理积累神经元并导致其变性。给定共享功能Acrosse。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但是，疾病。韧性。我们已经建立了比较果蝇和鼠标与年龄相关的神经退行性疾病的模型。物种提供了与年龄相关的神经变性的进化性细胞和分子途径的见解。 vglut2（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。响应于蝇和小鼠中α-突触核蛋白A的病理积累阐明vglut在DA神经元脆弱性中的作用，我们建立了一个杂货套件可选的工具可以区分和操纵苍蝇和错过的vglut的DA神经元工具和模型，我们现在可以回答关键问题：1）调节的保守机制是什么 da神经元中的vglut在突触性疾病中的表达和2）对突触性造成的神经变性的韧性吗？遗传障碍能够快速识别脆弱性和韧性的新目标，并在突触病的小鼠模型。调节性控制和所涉及的基因对于突触核病的VGLUT上心至关重要（AIM 1） vglut表达的上调是一种促生存的应对机制，是模块的基因 DA神经元中VGLUT的表达增加有助于突触核病的弹性（AIM 2）比较方法，我们确定了整个物种中保守的新型新型介入目标以提高 DA神经元中的韧性。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。