Exploring the Pathogenicity of CYLD Variants in FTD

额颞叶痴呆（FTD）是仅次于阿尔茨海默病（AD）的第二种最常见的痴呆形式， 是由额叶和/或前颞叶萎缩引起的。FTD的特征在于 人格，同情心丧失，冷漠，去抑制和语言障碍，在早期-中期阶段，和一般 后期的认知能力下降。FTD在临床、病理学和遗传学上与肌萎缩 侧索硬化症（ALS）和了解FTD的致病机制也有重要意义， AD. FTD潜在的分子和细胞机制知之甚少。高达50%的FTD是家族性的 并与至少15个不同功能基因的突变相关，这表明了一种强烈的遗传学特征。 成分值得注意的是，这些基因中至少有10个涉及自噬，一种保守的细胞质量- 将细胞质内容物输送到溶酶体进行降解的控制过程。自噬已经成为 FTD/ALS和其他主要神经退行性疾病的中心机制。但委员会仍 自噬在FTD/ALS中是如何失调的，以及自噬功能失调是如何确切地导致 疾病，提出了一个主要的障碍和知识差距，在发展基于自噬的治疗 战略布局最近，预测具有高致病潜力的CYLD基因的三种罕见变体， 在FTD/ALS患者中发现，CYLD是FTD/ALS致病基因家族的最新成员。 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， 调节自噬通量，表明CYLD在FTD相关自噬中的潜在作用。CYLD被称为 一种与家族性圆柱瘤病（头部和颈部的皮肤肿瘤）有关的肿瘤抑制因子， 信号，但其在神经元和突触中的作用在很大程度上是未知的。我们已发表和未发表的研究 表明CYLD是突触富集Lys 63特异性去泛素化酶，其在突触中具有主要作用 通过调节神经元自噬来维持、功能和可塑性。R21的目标 应用是描绘FTD连锁CYLD变异体的分子特征，并探索其 诱发FTD相关病理、突触丧失和功能障碍以及行为损伤的可能性。 我们的研究代表了首次尝试调查一个新的疾病基因在FTD发病机制中的作用。的 拟议中的研究具有根本的重要性和高度的意义，因为它们有可能 发现FTD/ALS及相关疾病的新遗传和分子机制以及治疗策略 痴呆

Frontotemporal dementia (FTD), the second most common form of dementia after Alzheimer’s disease (AD), is caused by atrophy of frontal and/or anterior temporal lobes. FTD is characterized by changes in personality, loss of empathy, apathy, disinhibition, and language disability at early-mid stages, and general cognitive deteriorations at later stages. FTD is linked clinically, pathologically, and genetically to amyotrophic lateral sclerosis (ALS) and understanding FTD pathogenic mechanisms also has significant implications for AD. Molecular and cellular mechanisms underlying FTD are poorly understood. Up to 50% of FTD are familial and associated with mutations of at least 15 genes of diverse functions, suggesting a strong genetic component. Remarkably, at least 10 of these genes are involved in autophagy, a conserved cell quality- control process that delivers cytoplasmic contents to lysosomes for degradation. Autophagy has emerged as a central mechanism in FTD/ALS and other major neurodegenerative diseases. 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, three rare variants of the CYLD gene, predicted to have high pathogenic potentials, are 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 that regulate autophagy flux, suggesting a potential role for CYLD in autophagy related to FTD. CYLD is known as a tumor suppressor linked to familial cylindromatosis (skin tumors in head and neck areas) and immune signaling, but its roles in neurons and synapses are largely unknown. Our published and unpublished studies indicate that CYLD is a synapse-enriched Lys63-specific deubiquitinase that has a major role in synapse maintenance, function, and plasticity through regulation of neuronal autophagy. The goals of this R21 application are to delineate the molecular characteristics of FTD-linked CYLD variants and explore their potentials to induce FTD-related pathologies, synapse loss and dysfunctions, and behavioral impairments. 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 genetic and molecular mechanisms and treatment strategies for FTD/ALS and related dementia.