Clonally expanded mitochondrial DNA deletions within the choroid plexus in multiple sclerosis

Area of Science:

• Neuroscience
• Cell Biology
• Pathology

Background:

• Mitochondrial DNA deletions (∆-mtDNA) are linked to neurodegenerative diseases like Alzheimer's (AD), Parkinson's (PD), and multiple sclerosis (MS), as well as aging.
• The choroid plexus, involved in MS inflammation, exposes mitochondria to oxidative stress, potentially promoting ∆-mtDNA accumulation.
• Clonal expansion of ∆-mtDNA signifies a rise in mutant mtDNA within a single cell.

Purpose of the Study:

• To investigate the prevalence of respiratory enzyme deficiency and ∆-mtDNA in choroid plexus epithelial cells across MS, AD, PD, and control groups at a single-cell level.
• To determine if clonal expansion of ∆-mtDNA is a significant feature in the choroid plexus, particularly in MS.

Main Methods:

• Single-cell analysis of choroid plexus epithelial cells.
• Assessment of respiratory enzyme deficiency (specifically Complex IV and Complex II activity).
• Quantification of ∆-mtDNA and its clonal expansion.

Main Results:

• Respiratory enzyme-deficient cells were more common in the choroid plexus of AD, MS, and PD patients compared to controls.
• A significantly higher proportion of these deficient cells in MS lacked the main catalytic subunit of Complex IV (cytochrome c oxidase subunit-I) compared to AD, PD, and controls.
• MS showed a fourfold increase in respiratory enzyme-deficient choroid plexus epithelial cells with clonally expanded ∆-mtDNA.

Conclusions:

• Clonal expansion of ∆-mtDNA is a more prominent feature in the choroid plexus epithelium of MS patients than in AD, PD, or controls.
• This expansion may serve as a molecular link connecting inflammation and delayed cellular energy failure in MS.
• The findings highlight the specific role of the choroid plexus in MS pathogenesis related to mitochondrial dysfunction.