CHCHD10^S59L/+ mouse model: Behavioral and neuropathological features of frontotemporal dementia

Area of Science:

• Neuroscience
• Genetics
• Mitochondrial Biology

Background:

• CHCHD10-related diseases present with diverse neurological and cardiac symptoms, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Understanding the mechanisms linking mitochondrial dysfunction to neurodegeneration is crucial for developing effective treatments.

Purpose of the Study:

• To comprehensively assess the behavioral, electrophysiological, and neuropathological characteristics of a novel Chchd10 knock-in mouse model (Chchd10^S59L/+).
• To establish the utility of this mouse model for studying CHCHD10-related FTD and for preclinical therapeutic testing.

Main Methods:

• Generation of Chchd10^S59L/+ knock-in mice.
• Behavioral testing assessing learning and memory.
• Electrophysiological recordings of long-term potentiation (LTP) at hippocampal synapses.
• Neuropathological examination of brain tissue, focusing on protein aggregates, integrated stress response (ISR), and neuroinflammation.

Main Results:

• Chchd10^S59L/+ mice exhibited impaired learning and memory, with reduced LTP in the hippocampus.
• Neuropathological analysis revealed protein aggregates, ISR activation, and neuroinflammation in the hippocampus of these mice.
• The mouse model recapitulated key features of CHCHD10-related disorders, including myopathy, cardiomyopathy, and ALS pathology.

Conclusions:

• The Chchd10^S59L/+ mouse model accurately replicates the multifaceted pathology of CHCHD10-related diseases, including FTD.
• This model provides a valuable platform for investigating the molecular mechanisms underlying CHCHD10-associated neurodegeneration.
• The Chchd10^S59L/+ mice are suitable for preclinical evaluation of therapeutic strategies for FTD and related disorders.