Functional role of Sec20, a BH3 and Secretory (Sec) domain protein, in neurons and its relevance to a motor neuron disease in Drosophila

Sec20（一种 BH3 和分泌 (Sec) 结构域蛋白）在神经元中的功能作用及其与果蝇运动神经元疾病的相关性

• 批准号: 10635856
• 负责人: KRISHNA MOORTHI BHAT
• 金额: $ 141.7万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635856
• 关键词: Adenoviruses; Adult; Affect; Amyotrophic Lateral Sclerosis; Apoptosis; Apoptotic; Autophagocytosis; Autophagosome; BCL2 gene; Bioenergetics; Biological Models; Biology; Brain; Brain Diseases; C9ORF72; Cell Death; Cessation of life; Chromosomes; Citrate (si)-Synthase; Collaborations; Data; Defect; Dementia; Development; Disease; Drosophila genus; Eye; Failure; Female; Frontotemporal Dementia; Genes; Genetic; Genetic Models; Glutamates; Goals; HRK gene; Health; Human; Knowledge; Link; Lysosomes; Mediating; Mission; Mitochondria; Molecular; Molecular Biology; Motor Neuron Disease; Motor Neurons; Movement; Mutation; Nervous System; Neurobiology; Neurodegenerative Disorders; Neurology; Neurons; Open Reading Frames; Orthologous Gene; Pathology; Patients; Phenotype; Play; Protein Family; Proteins; Public Health; Publishing; Reporting; Risk Factors; Role; Sampling; Superoxide Dismutase; System; Techniques; Tertiary Protein Structure; United States National Institutes of Health; Work; cell transformation; fly; frontotemporal lobar dementia amyotrophic lateral sclerosis; gene function; genome wide association study; insight; knock-down; loss of function; male; member; mitochondrial dysfunction; motor deficit; motor disorder; motor neuron function; mouse model; mutant; nervous system disorder; neuron apoptosis; neuron loss; neuronal survival; prevent; pro-apoptotic protein; recruit; tool

This proposal examines the functional role of Sec20, a BH3 and Secretory (Sec) domain protein, in neurons and its relevance to a motor neuron disease using Drosophila. It also examines the interaction between sec20 and GGGGCC (G4C2) repeats of the gene C9orf72 (Chromosome9 open reading frame), a well- known mutation that causes Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) in humans. ALS-FTD are two progressive, adult-onset neurodegenerative diseases, often occurring together. The particular focus of this proposal is neuronal loss and mitochondrial and autophagy defects in the brain. Dysfunctional mitochondria and autophagic failures have emerged as important factors in neurodegenerative diseases. They may actively mediate these diseases or exacerbate them. sec20 is the ortholog of vertebrate Bnip1 gene, which is a member of the Bcl2 interacting protein family. Bnip1 has been tentatively identified as a risk factor for ALS and FTD in humans. We found that loss of function for sec20 in the CNS in Drosophila caused severe motor neuron disease and death. There was neuronal loss, mitochondrial dysfunction and autophagic failures in these flies. The disease and these molecular features had similarities to the motor deficits disease caused by the expression of G4C2 repeats. The phenotypes caused by the G4C2 repeats were upstream of sec20 in flies as well as in humans. Thus, our specific aims are: 1) Determine the molecular basis for the loss of motor neurons in sec20 mutant flies, 2) Determine if defective mitophagy and autophagy in sec20 mutants contribute to the disease, and 3) Delineate the interaction between sec20 and the c9orf72-G4C2-R in the CNS. In Drosophila, we go from phenotypes to genes and then molecular underpinnings. There is always a bottom line with this system. Our aims investigate the basics of the phenotypes caused by these genes/mutations. These studies will help understand the function of Sec20 in the CNS and how it relates to G4C2 repeats in the biology and in the diseases of the brain.

该提案研究了 Sec20（一种 BH3 和分泌 (Sec) 结构域蛋白）在 神经元及其与果蝇运动神经元疾病的相关性。它还检查交互作用 位于 sec20 和 GGGGCC (G4C2) 基因 C9orf72（Chromosome9 开放阅读框）重复序列之间，这是一个良好的 导致肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 的已知突变 人类。 ALS-FTD 是两种进行性、成人发病的神经退行性疾病，通常同时发生。这 该提案的特别关注点是大脑中的神经元丢失以及线粒体和自噬缺陷。 线粒体功能障碍和自噬失败已成为重要因素 神经退行性疾病。它们可能会主动介导这些疾病或加剧这些疾病。 sec20 是脊椎动物 Bnip1 基因的直系同源物，Bnip1 基因是 Bcl2 相互作用蛋白的成员 家庭。 Bnip1 已被初步确定为人类 ALS 和 FTD 的危险因素。我们发现损失 果蝇中枢神经系统中 sec20 功能的丧失导致严重的运动神经元疾病和死亡。那里 这些果蝇的神经元丢失、线粒体功能障碍和自噬失败。疾病和这些 分子特征与G4C2重复表达引起的运动缺陷疾病有相似之处。这 在果蝇和人类中，由 G4C2 重复序列引起的表型位于 sec20 的上游。 因此，我们的具体目标是：1）确定 20 秒内运动神经元丢失的分子基础 突变果蝇，2) 确定 sec20 突变体中缺陷的线粒体自噬和自噬是否有助于 疾病，3) 描述中枢神经系统中 sec20 和 c9orf72-G4C2-R 之间的相互作用。 在果蝇中，我们从表型到基因，然后是分子基础。总有一个 这个系统的底线。我们的目标是研究由这些引起的表型的基础知识 基因/突变。这些研究将有助于了解 Sec20 在 CNS 中的功能及其与 G4C2 在生物学和大脑疾病中重复出现。