An atlas of the aging glycoproteome reveals how glycosylation modulates autoantibody binding in the brain

A comprehensive study has mapped the N-glycoproteome across various organs of mice at different ages, shedding light on how glycosylation changes with aging. The research, published in the glycoproteome atlas (glycoproteinatlas.org), reveals that organ identity is the primary factor influencing glycan composition, while specific glycosites undergo remodeling as organisms grow older.

The brain, in particular, exhibits a notable increase in short paucimannose glycans with age. This change is partly attributed to the elevation of the glycan-processing enzyme HEXB, which is itself associated with aging. Within the brain, white matter serves as a critical hotspot for this phenomenon. Aging in this region leads to heightened paucimannosylation of Myelin oligodendrocyte glycoprotein (MOG), a protein frequently targeted by central nervous system autoantibodies.

The researchers identified MOG-reactive autoantibodies in both aged individuals and patients suffering from MOG antibody-associated disease (MOGAD). Further analysis demonstrated that the glycan present at MOG N60 plays a pivotal role in modulating the binding of these autoantibodies. Interestingly, experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, mirrored several of the age-related glycosite alterations observed in the study.

This finding suggests that shared glycosylation signatures exist between aging and autoimmune processes targeting MOG.

In summary, this groundbreaking study establishes N-glycosylation as both a chronological marker and a regulatory mechanism in molecular interactions. The findings not only provide new insights into the aging process but also offer potential pathways for understanding and treating autoimmune diseases targeting MOG.