Sex differences in the neuronal transcriptome and synaptic mitochondrial function in the cerebral cortex of a...

Area of Science:

• Neuroscience
• Immunology

Background:

• Multiple sclerosis (MS) impacts the cerebral cortex, causing atrophy and neuronal damage.
• While women are more prone to MS, men experience more severe disability progression.

Purpose of the Study:

• To investigate sex differences in neurodegenerative mechanisms within the cerebral cortex using a mouse model of MS.
• To identify molecular and cellular pathways contributing to worse neurodegeneration in male MS patients.

Main Methods:

• Utilized RNA sequencing (RiboTag) on cerebral cortex neurons from male and female mice with chronic experimental autoimmune encephalomyelitis (EAE) and controls.
• Assessed mitochondrial morphology in neurons using Thy1-CFP-MitoS mice.
• Measured oxygen consumption rates in synaptosomes via mitochondrial respirometry.

Main Results:

• Male EAE mice exhibited significant differential gene expression in cortical neurons, primarily linked to mitochondrial dysfunction and oxidative phosphorylation.
• Abnormalities in neuronal mitochondrial morphology and decreased synaptosomal oxygen consumption were observed in male EAE mice, but not in females.
• Transcriptomic and functional analyses revealed more severe neurodegeneration in the cerebral cortex of male EAE mice compared to females.

Conclusions:

• Cortical neurodegeneration is more pronounced in male mice with EAE, characterized by mitochondrial dysfunction.
• These findings in the EAE model mirror the worse disability progression seen in men with MS.
• The study identifies potential therapeutic targets for preventing cortical neurodegeneration and mitigating disability in MS men.