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

• 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
• 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' 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

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 阿尔茨海默病（AD）是阿尔茨海默病（AD）后的一种常见痴呆症，目前尚无治愈方法。FTD由以下原因引起 额叶和/或前颞叶皮质局灶性但进行性萎缩，导致性格改变， 早中期的冷漠、移情丧失、去抑制和语言障碍，以及一般记忆和 认知能力下降，后期需要全时护理。因此，人们认为， 前驱期突触和回路功能障碍，潜在的行为障碍可能先于大规模的晚期- 神经元细胞丧失和残疾。然而，FTD相关的分子机制 导致疾病发生和发展的突触病变还没有被很好地理解。FTD连接 在临床上、病理学上、遗传学上和机制上与肌萎缩性侧索硬化症（ALS）相关。高达50%的 FTD具有家族性，与至少15种不同功能基因的突变相关。值得注意的是，至少 其中10个基因参与自噬，自噬已成为FTD/ALS的核心机制。 然而，自噬在FTD/ALS中是如何失调的，以及自噬在FTD/ALS中究竟是如何失调的， 功能障碍导致疾病，这是发展中的一个主要障碍和知识差距， 自噬治疗策略。最近，在CYLD基因中发现了一个功能获得性突变 在FTD/ALS患者中，将CYLD作为FTD/ALS致病基因家族的最新成员。CYLD 编码Lys 63特异性去泛素化酶，并与几种FTD基因产物相互作用，包括 p62/SQSTM 1、视神经磷酸酶和TBK 1，表明CYLD在FTD相关自噬中的潜在作用。 CYLD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，但其 在神经元和突触中的作用知之甚少。我们已发表和正在进行的研究表明，CYLD 是一种丰富的Lys 63特异性突触去泛素化酶，在突触维持中起主要作用， 功能和可塑性通过调节神经元自噬。此R 01应用程序的目标是 定义突触中CYLD依赖性自噬的分子细节和功能后果 重塑（目的1），以表征新产生的可诱导和可逆的转基因小鼠模型 携带FTD致病突变CYLDM 719 V的FTD发病机制（目的2），并研究 CYLDM 719 V在FTD中致病作用及在人诱导多能干细胞中的治疗策略探索 细胞（iPSC）衍生的皮质神经元（Aim 3）。我们的研究代表了第一次尝试调查的作用， FTD发病机制中的新疾病基因。拟议的研究具有根本的重要性和高度 意义重大，因为它们有可能揭示新的致病机制和治疗方法 FTD和相关神经退行性疾病的治疗策略。