# Exploring the Pathogenicity of CYLD Variants in FTD

> **NIH NIH R21** · UPSTATE MEDICAL UNIVERSITY · 2021 · $463,750

## Abstract

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 Our published and unpublished studies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.

## Key facts

- **NIH application ID:** 10391941
- **Project number:** 1R21NS125845-01
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Wei-Dong Yao
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $463,750
- **Award type:** 1
- **Project period:** 2021-09-29 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10391941

## Citation

> US National Institutes of Health, RePORTER application 10391941, Exploring the Pathogenicity of CYLD Variants in FTD (1R21NS125845-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10391941. Licensed CC0.

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