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 Our published and unpublished studies indicate that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.