CYLD in Synapse Pruning and Pathogenesis of FTD

CYLD 在突触修剪和 FTD 发病机制中的作用

• 批准号: 10419643
• 负责人: Wei-Dong Yao
• 金额: $ 68.22万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10419643
• 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; CRISPR/Cas technology; Caring; Cell Death; Cell Line; Chronic; Clinical; Cognitive; Dementia; Deterioration; Development; Disease; Disease Progression; Disinhibition; Electrophysiology (science); Empathy; Enzymes; Excitatory Synapse; Exhibits; FRAP1 gene; Familial Dementias; Frontotemporal Dementia; Functional disorder; Gene Family; Genes; Goals; Hippocampus (Brain); Human; Immune signaling; Impairment; Knockout Mice; Knowledge; Language Disorders; Link; Maintenance; Mediating; Memory; Mental Depression; Molecular; Morphology; Mus; Mutation; Neurodegenerative Disorders; Neurons; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Personality; Phenotype; Play; Polyubiquitin; Prefrontal Cortex; Prosencephalon; Proteins; Publishing; Regulation; Role; Signal Transduction; Symptoms; Synapses; Synaptic plasticity; TBK1 gene; Temporal Lobe; Testing; Therapeutic; Time; Transgenes; Transgenic Mice; Tumor Suppressor Proteins; age related; aged; astrogliosis; base; 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; interdisciplinary approach; mTOR Inhibitor; member; mouse model; multicatalytic endopeptidase complex; multidisciplinary; mutant; neural circuit; neuron loss; neurotoxicity; novel; novel strategies; protein TDP-43; proteostasis; scaffold; social; stem cell model; synaptic function; synaptogenesis; treatment strategy

Frontotemporal dementia (FTD) is the leading dementia before the age of 65 and the second most common form of dementia after Alzheimer’s disease (AD). 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. Thus, synaptic and circuit dysfunctions underlying behavior impairments may precede massive neuronal cell loss and disability. However, molecular mechanisms underlying disease initiation and early symptoms as well as disease 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 deubiquiting 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 largely unknown. Our published and unpublished 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 (Aim 1), to generate an inducible transgenic mouse model and delineate the role of FTD-causing mutation CYLDM719V in FTD pathogenesis (Aim 2), and to validate 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. Our 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65岁以前的主要痴呆症，也是第二常见的痴呆症 阿尔茨海默病（AD）后的痴呆形式。无药可救。FTD是由局灶性但进行性的 额叶和/或前颞叶皮质萎缩，导致个性改变，冷漠，丧失 移情，去抑制和语言障碍在早中期阶段，和一般记忆和认知 在后期需要全时护理的恶化。因此，突触和电路功能障碍的基础 行为损伤可能先于大量神经元细胞损失和残疾。然而，分子 疾病发生和早期症状以及疾病进展的潜在机制尚不清楚， 明白FTD在临床、病理、遗传和机制上与肌萎缩侧索硬化相关。 硬化症（ALS）。高达50%的FTD是家族性的，与至少15个不同基因的突变相关。 功能协调发展的值得注意的是，这些基因中至少有10个与自噬有关，自噬已经成为一个核心的 FTD/ALS中的机制。然而，自噬在FTD/ALS中是如何失调的， 正是自噬功能障碍导致的疾病，提出了一个主要的障碍和知识差距， 开发基于自噬的治疗策略。最近，CYLD中的功能突变的获得 在FTD/ALS患者中鉴定出CYLD基因，将CYLD作为FTD/ALS致病基因的最新成员 家人CYLD编码一种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在与细胞凋亡相关的自噬中的潜在作用。 FTD。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， 其在神经元和突触中的作用在很大程度上未知。我们已发表和未发表的研究表明， 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CYLD依赖性自噬的分子细节和功能后果（目标1）， 产生可诱导的转基因小鼠模型，并描述引起FTD的突变CYLDM 719 V在 FTD发病机制（目的2），并验证CYLDM 719 V在FTD中的致病作用，探索治疗 在人诱导多能干细胞（iPSC）衍生的皮质神经元中的免疫策略（Aim 3）。我们的研究 代表了首次尝试研究新疾病基因在FTD发病机制中的作用。我们提出的 这些研究具有根本的重要性和高度的意义，因为它们有可能揭示新的 FTD和相关神经退行性疾病的致病机制和治疗策略。