Elevating Neuronal CYLD Causes Frontotemporal Dementia (FTD)-Relevant Behavioral and Physiological Deficits

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Frontotemporal dementia (FTD) is a neurodegenerative disease linked to genetic mutations.
• The CYLD gene, encoding a deubiquitinating enzyme, is implicated in FTD.
• A specific CYLD variant (M719V) is suspected to be pathogenic, but its in vivo effects are unknown.

Purpose of the Study:

• To investigate the in vivo pathogenicity of the M719V-CYLD mutation.
• To elucidate the underlying molecular and cellular mechanisms of FTD associated with CYLD.
• To develop a novel transgenic mouse model for studying FTD.

Main Methods:

• Adeno-associated virus (AAV) mediated somatic brain transgenesis to express wildtype (WT) or M719V-CYLD in mouse neurons.
• Behavioral assessments to evaluate FTD-associated impairments (risk-taking, social interaction, empathy).
• Neurophysiological recordings in the prefrontal cortex (PFC) and molecular analyses (autophagy, Akt-mTOR signaling).

Main Results:

• Mice expressing M719V-CYLD exhibited significant FTD-like behavioral deficits and neurophysiological impairments in the PFC.
• Elevated autophagy and decreased Akt-mTOR signaling were observed in M719V-CYLD mouse brains.
• WT-CYLD expression partially recapitulated these phenotypes, suggesting CYLD activation contributes to deficits and M719V is gain-of-function.

Conclusions:

• Neuronal CYLD plays a crucial role in PFC function and social behaviors.
• The M719V mutation in CYLD is pathogenic and gain-of-function, contributing to FTD.
• This study provides a valuable mouse model for investigating FTD pathogenesis at multiple levels.