A protective variant of the autophagy receptor CALCOCO2/NDP52 in Multiple Sclerosis (MS)

Area of Science:

• Neuroimmunology
• Cellular Biology
• Genetics

Background:

• Multiple sclerosis (MS) is an autoimmune central nervous system disease linked to mitochondrial dysfunction.
• Mitophagy, the clearance of damaged mitochondria, is crucial for cellular health and has been implicated in MS pathogenesis.
• Understanding the molecular mechanisms of MS requires investigation into pathways like mitophagy.

Purpose of the Study:

• To investigate the role of mitophagy and its regulatory proteins in peripheral blood mononuclear cells (PBMCs) of MS patients.
• To identify genetic factors associated with MS that influence mitochondrial quality control pathways.
• To explore the function of the autophagic receptor CALCOCO2/NDP52 in the context of MS.

Main Methods:

• Genetic analysis of CALCOCO2/NDP52 in 203 MS patients and 1000 healthy controls.
• Structural modeling and functional studies of a specific CALCOCO2 variant (G140E).
• Analysis of CALCOCO2 expression and mitophagy function in PBMCs, particularly B cells.

Main Results:

• A natural variant of CALCOCO2/NDP52 was identified and found to be associated with and protective in MS.
• The protective variant features an amino acid substitution (G140E) near the LC3-interacting region (LIR) motif, impacting mitophagy control.
• CALCOCO2 is predominantly expressed in B cells within PBMCs, where it mediates mitophagy to reduce pro-inflammatory cytokine production.

Conclusions:

• CALCOCO2/NDP52 plays a significant role in regulating mitophagy, with a specific variant conferring protection against MS.
• The protective function of CALCOCO2 in B cells, through mitophagy, suggests a novel therapeutic target for autoimmune diseases like MS.
• These findings highlight a new link between mitochondrial quality control, B cell function, and the pathogenesis of multiple sclerosis.