Exploring the Pathogenicity of CYLD Variants in FTD

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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 Our published and unpublished studies indicate that CYLD is a synapse-enriched Lys63-specific deubiquitinase that has a major role in synapse maintenance, function, and plasticity through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.