Synaptopathy and Pathogenesis in Frontotemporal Dementia: Role of CYLD

额颞叶痴呆的突触病和发病机制：CYLD 的作用

基本信息

批准号：
10680953
负责人：
Fen-Biao Gao
金额：
$ 236.4万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680953
关键词：
ALS patients Adult Age Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Anterior Anxiety Appearance Atrophic Autophagocytosis Autophagosome Behavior Behavioral Binge Eating Biochemical Brain Caring Cell Death Cell Line Chronic Clinical Cognitive Defect Dementia Deterioration Deubiquitinating Enzyme Development Disease Disinhibition Electrophysiology (science)Empathy Enzyme Interaction Excitatory Synapse Exhibits FRAP1 gene Familial Dementias Frontotemporal Dementia Functional disorder Gene Family Genes Goals Hippocampus Human Immune signaling Impairment Knockout Mice Knowledge Language Disorders Link Lysosomes Maintenance Mediating Memory Mental Depression Molecular Mus Mutation Neurodegenerative Disorders Neurons Onset of illness Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Personality Phenotype Play Polyubiquitin Prefrontal Cortex Prosencephalon Proteins Psychiatry Publishing Regulation Role Signal Transduction Synapses Synaptic plasticity TBK1 gene Temporal Lobe Testing Therapeutic Transgenes Transgenic Mice Tumor Suppressor Proteins age related aged astrogliosis behavioral impairment behavioral variant frontotemporal dementia disability enzyme activity excitatory neuron experimental study frontotemporal lobar dementia amyotrophic lateral sclerosis gain of function mutation gene product in vivo induced pluripotent stem cell inhibitor language impairment member mouse model multicatalytic endopeptidase complex mutant neuron loss neurotoxicity novel novel strategies protein TDP-43 proteostasis scaffold social stem cell model synaptic function synaptogenesis treatment strategy ubiquitin isopeptidase

项目摘要

Frontotemporal dementia (FTD) is the leading cause of dementia before the age of 60 and the second most common form of dementia overall after Alzheimer’s disease (AD), and there is no cure. FTD is caused by focal but progressive atrophy of frontal and/or anterior temporal cortices that leads to changes in personality, apathy, loss of empathy, disinhibition, and language disability at early-mid stages, and general memory and cognitive deteriorations requiring a full-time care at later stages. Consistently, it is thought that early prodromal synaptic and circuit dysfunctions underlying behavior impairments may precede massive late- onset neuronal cell loss and disability. However, molecular mechanisms underlying FTD-associated synaptopathies that contribute to disease initiation and progression are not well understood. FTD is linked clinically, pathologically, genetically, and mechanistically to amyotrophic lateral sclerosis (ALS). Up to 50% of FTD are familial and associated with mutations of at least 15 genes of diverse functions. Remarkably, at least 10 of these genes are involved in autophagy, which has emerged as a central mechanism in FTD/ALS. However, it remains enigmatic how autophagy is dysregulated in FTD/ALS and how exactly autophagy dysfunctions cause the diseases, presenting a major hurdle and knowledge gap in development of autophagy-based therapeutic strategies. Recently, a gain of function mutation in the CYLD gene is identified in FTD/ALS patients, placing CYLD as the newest member of the FTD/ALS-causing gene family. CYLD encodes a Lys63-specific deubiquitinating enzyme and interacts with several FTD gene products, including p62/SQSTM1, Optineurin, and TBK1, suggesting a potential role for CYLD in autophagy related to FTD. CYLD is best known as a tumor suppressor linked to familial cylindromatosis and immune signaling, but its roles in neurons and synapses are poorly understood. Our published and ongoing studies indicate that CYLD is an abundant Lys63-specific synaptic deubiquitinase that has a major role in synapse maintenance, function, and plasticity through regulation of neuronal autophagy. The goals of this R01 application are to define the molecular details and functional consequences of CYLD-dependent autophagy in synapse remodeling (Aim 1), to characterize a newly generated inducible and reversable transgenic mouse model carrying the FTD-causing mutation CYLDM719V in FTD pathogenesis (Aim 2), and to investigate the pathogenic role of CYLDM719V in FTD and explore therapeutic strategies in human induced pluripotent stem cell (iPSC)-derived cortical neurons (Aim 3). Our study represents the first attempt to investigate the role of a new disease gene in FTD pathogenesis. The proposed studies are fundamentally important and highly significant because they have the potential to uncover novel pathogenic mechanisms and treatment strategies for FTD and related neurodegenerative diseases.

额颞叶痴呆 (FTD) 是 60 岁之前痴呆的主要原因，也是第二大原因继阿尔茨海默病 (AD) 后，常见的痴呆症是由 FTD 引起的。额叶和/或前颞叶皮质局灶性但进行性萎缩，导致性格变化，早中期的冷漠、同理心丧失、抑制解除和语言障碍以及一般记忆力和人们一致认为，后期阶段认知能力下降需要全职护理。潜在的行为障碍的前驱期突触和回路功能障碍可能先于大规模的晚期行为然而，FTD 相关的分子机制。导致疾病发生和进展的突触病之间的联系尚不清楚。临床上、病理学上、遗传上和机械上的肌萎缩侧索硬化症 (ALS) 高达 50%。 FTD 具有家族性，并且与至少 15 个不同功能的基因突变相关。其中 10 个基因与自噬有关，自噬已成为 FTD/ALS 的核心机制。然而，自噬在 FTD/ALS 中如何失调以及自噬到底如何发生仍然是个谜。功能障碍会导致疾病，这给疾病的发展带来了主要障碍和知识差距最近，发现了 CYLD 基因的功能突变。在 FTD/ALS 患者中，CYLD 成为 FTD/ALS 致病基因家族的最新成员。编码 Lys63 特异性去泛素化酶并与多种 FTD 基因产物相互作用，包括 p62/SQSTM1、Optineurin 和 TBK1，表明 CYLD 在与 FTD 相关的自噬中具有潜在作用。 CYLD 最出名的是一种与家族性圆柱瘤病和免疫信号相关的肿瘤抑制因子，但它的我们已发表和正在进行的研究表明 CYLD 在神经元和突触中的作用知之甚少。是一种丰富的 Lys63 特异性突触去泛素酶，在突触维持中起重要作用， R01 应用的目标是通过调节神经元自噬来实现功能和可塑性。定义突触中 CYLD 依赖性自噬的分子细节和功能后果重塑（目标 1），表征新生成的可诱导且可逆的转基因小鼠模型在 FTD 发病机制中携带导致 FTD 的突变 CYLDM719V（目标 2），并研究 CYLDM719V 在 FTD 中的致病作用及探索人诱导多能干细胞的治疗策略我们的研究代表了研究细胞（iPSC）来源的皮质神经元的作用的首次尝试。 FTD 发病机制中的新疾病基因所提出的研究具有根本性的重要意义和高度。意义重大，因为它们有可能发现新的致病机制和治疗方法 FTD 和相关神经退行性疾病的策略。