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Cell autonomous and non autonomous induction of degeneration in Drosophila

果蝇细胞自主和非自主诱导变性

基本信息

批准号：
10343843
负责人：
JAMES A MCNEW
金额：
$ 39.03万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343843
关键词：
Adult Alzheimer&apos s Disease Attenuated Autophagocytosis Binding Proteins Biological Assay Cells Chest Chimeric Proteins Chronic Data Denervation Disease Disuse Atrophy Drosophila genus Dwarfism Functional disorder Gene Dosage Generations Genes Genetic Transcription Glutamate Receptor Glutamates Hereditary Spastic Paraplegia Homeostasis Human Pathology Insulin Investigation Link MAP Kinase Kinase Kinase MAPK8 gene Mediating Medical Modeling Molecular Motor Neurons Muscle Muscular Atrophy Nerve Degeneration Neuromuscular Junction Neurons Organism Oxidative Stress Parkinson Disease Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphorylation Phosphorylation Inhibition Phosphotransferases Polyubiquitin Process Protein Biosynthesis Proteins Reactive Oxygen Species Role Sepsis Signal Pathway Signal Transduction Signaling Molecule Sirolimus Spastic Paraplegia Stress Synapses Synaptic Transmission Testing Ubiquitin Work age related attenuation base biological adaptation to stress cancer cachexia cytotoxic experimental study glutamatergic signaling inhibition of autophagy inhibitor insight insulin signaling knock-down locomotor deficit mitochondrial dysfunction muscle degeneration mutant neuromuscular transmission neuron loss novel therapeutic development

项目摘要

Project Summary Degeneration of neurons or muscle are observed in several human pathologies, including Alzheimer's, Parkinson's and the hereditary spastic paraplegias (HSP) for neuronal degeneration, and disuse atrophy, cancer cachexia, and sepsis for muscle degeneration. Despite many recent advances, the molecular mechanism(s) underlying these degenerative processes remain incompletely understood. To generate such mechanistic insights, the PIs have recently established a Drosophila model for the HSPs. The specific focus is in atlastin (atl, Spastic Paraplegia Gene 3A), which encodes an ER fusion protein. Based on the previous observation that atl knockdown in neurons causes progressive, age-dependent locomotor deficits, the we asked if this knockdown also caused progressive cellular degeneration. Investigations into the adult thoracic musculature revealed that atl loss from either neuron or muscle caused progressive degeneration associated with a number of other pathologies including accumulation of aggregates containing ubiquitin, increased reactive oxygen species (ROS), and activation of the JNK/Foxo stress response pathway. Administering the drug rapamycin, which inhibits the Tor kinase, or decreasing Tor gene dosage reversed many of these pathologies at least partially, indicating that atl loss might activate muscle Tor. Muscle Tor and Foxo activation have also been observed in denervation-induced muscle atrophy. In this application, experiments are proposed to elucidate the mechanisms by which atl loss causes progressive muscle pathologies. Aim #1 will test the hypothesis that muscle Tor is activated by atl loss, determine if Tor activity is sufficient as well as necessary for atl loss phenotypes, and test the prediction that Tor activity promotes muscle degeneration by inhibiting autophagy. Aim #2 will examine the causal relationship between activated Tor and increased ROS, and between ROS and the JNK/Foxo stress pathway. In particular, we will test two non-mutually exclusive hypotheses explaining Foxo activation; first, that activated Tor increases ROS, which in turn is responsible for JNK activation, and finally Foxo activation, and second, that activated Tor activates its target S6K, which in turn down-regulates insulin signaling, thus decreasing activity of the Foxo inhibitor Akt. Aim #3 will test the hypothesis that neuronal atl loss activates muscle Tor by attenuating glutamatergic neuromuscular transmission. In particular, it will be determined if deletion of one glutamate receptor, previously shown to be sufficient to activate muscle Tor, will cause similar muscle pathologies as is observed by neuronal atl knockdown. In addition, it will be determined if neuronal atl loss confers neuronal phenotypes similar to those conferred by glutamate receptor deletion. Successful completion of these experiments will provide novel and critical mechanistic insights linking defective synaptic input conferred by atl loss to muscle degeneration. The PIs anticipate that these experiments will also provide mechanistic insights applicable to neuronal degeneration as well, which will give these experiments a broad medical relevance.

项目概要在多种人类疾病中观察到神经元或肌肉的退化，包括阿尔茨海默病、帕金森氏症和遗传性痉挛性截瘫（HSP）导致神经元变性和废用性萎缩，癌症恶病质和肌肉变性败血症。尽管最近取得了许多进展，但分子这些退化过程背后的机制仍不完全清楚。为了生成这样的基于机制见解，PI 最近建立了 HSP 的果蝇模型。具体重点是 atlastin（atl，痉挛性截瘫基因 3A），编码 ER 融合蛋白。基于之前的观察到神经元中 atl 敲低会导致进行性、年龄依赖性运动缺陷，我们询问这种敲低是否也会导致进行性细胞退化。成人胸廓检查肌肉系统显示，神经元或肌肉的 atl 损失导致了相关的进行性退化与许多其他病理学，包括含有泛素的聚集物的积累，增加活性氧 (ROS) 和 JNK/Foxo 应激反应途径的激活。管理雷帕霉素药物可抑制 Tor 激酶，或减少 Tor 基因剂量可逆转其中许多问题至少部分病理学表明 atl 损失可能会激活肌肉 Tor。 Muscle Tor 和 Foxo 激活在去神经引起的肌肉萎缩中也观察到了这种现象。在此应用中，提出了实验阐明 atl 缺失导致进行性肌肉病变的机制。目标 #1 将测试假设肌肉 Tor 是由 atl 损失激活的，确定 Tor 活动对于 atl 丢失表型，并测试 Tor 活性通过抑制促进肌肉退化的预测自噬。目标 #2 将检查激活的 Tor 和 ROS 增加之间的因果关系，以及 ROS 和 JNK/Foxo 应激通路之间的关系。特别是，我们将测试两个非互斥的解释 Foxo 激活的假设；首先，激活的 Tor 会增加 ROS，而 ROS 又负责 JNK 激活，最后 Foxo 激活，其次，激活的 Tor 激活其目标 S6K，其中下调胰岛素信号传导，从而降低 Foxo 抑制剂 Akt 的活性。目标 #3 将测试假设神经元 atl 损失通过减弱谷氨酸能神经肌肉来激活肌肉 Tor 传播。特别是，将确定先前显示的一种谷氨酸受体的缺失是否会导致足以激活肌肉 Tor，将导致与神经元 atl 观察到的类似的肌肉病理击倒。此外，还将确定神经元 atl 丢失是否会赋予与那些类似的神经元表型谷氨酸受体缺失所致。这些实验的成功完成将提供新颖且将 atl 损失导致的突触输入缺陷与肌肉退化联系起来的关键机制见解。这 PI 预计这些实验还将提供适用于神经元的机制见解变性也是如此，这将使这些实验具有广泛的医学意义。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Drosophila melanogaster attP40 docking site and derivatives are insertion mutations of msp-300.

DOI：
10.1371/journal.pone.0278598
发表时间：
2022
期刊：
PLOS ONE
影响因子：
3.7
作者：
van der Graaf, Kevin;Srivastav, Saurabh;Singh, Pratibha;McNew, James A.;Stern, Michael
通讯作者：
Stern, Michael

A transition to degeneration triggered by oxidative stress in degenerative disorders.