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症形式， 是由额叶和/或前颞叶萎缩引起的。FTD的特点是在 人格、同理心丧失、冷漠、去抑制和语言障碍，以及一般 认知功能在后期的恶化。FTD在临床、病理和遗传上都与肌营养不良有关。 侧索硬化症(ALS)和了解FTD的发病机制也对 广告。FTD背后的分子和细胞机制尚不清楚。高达50%的FTD是家族成员 并与至少15个具有不同功能的基因的突变有关，这表明 组件。值得注意的是，其中至少有10个基因参与了自噬，这是一种保守的细胞质量- 将细胞质内容物运送到溶酶体进行降解的控制过程。自噬现象已经成为 FTD/ALS和其他主要神经退行性疾病的中心机制。然而，它仍然 自噬是如何在FTD/ALS中失控的，以及自噬失灵究竟是如何导致 疾病，是发展基于自噬的治疗方法的主要障碍和知识差距 战略。最近，被预测具有高致病潜力的三种罕见的CyLD基因变体是 在FTD/ALS患者中发现，使CyLD成为FTD/ALS致病基因家族的最新成员。 CyLD编码Lys63特异的脱泛素化酶，并与几种FTD基因产物相互作用 调节自噬通量，提示CyLD在与FTD相关的自噬中可能发挥作用。CyLD被称为 一种与家族性圆柱瘤病(头颈部皮肤肿瘤)和免疫有关的肿瘤抑制因子 信号，但它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 提示CyLD是一种富含突触的Lys63特异性脱泛素酶，在突触中起重要作用 通过调节神经元自噬来维持、功能和可塑性。这款R21的目标是 应用是描绘FTD连接的CyLD变异体的分子特征并探索它们的 可能导致FTD相关的病理、突触丢失和功能障碍以及行为障碍。 我们的研究是首次尝试研究新的疾病基因在FTD发病机制中的作用。这个 拟议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及治疗策略 痴呆症。

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.