An atlas of the aging glycoproteome reveals how glycosylation modulates autoantibody binding in the brain
Abstract
N-glycosylation generates substantial molecular diversity, yet how glycan composition varies throughout aging remains poorly understood. We mapped the N-glycoproteome of brain, liver, spleen, kidney, and plasma across nine ages spanning the mouse lifespan, identifying 80,618 unique N-glycopeptides at 9,211 glycosites on 4,391 glycoproteins, together with matched proteomic trajectories (glycoproteinatlas.org). Organ identity was the dominant determinant of glycan composition, but numerous glycosites nevertheless underwent remodeling with age. The brain showed a prominent age-associated increase in short paucimannose glycans, driven in part by the age-associated increase in the glycan-processing enzyme HEXB. In white matter, a hotspot for this change, aging increased the paucimannosylation of Myelin oligodendrocyte glycoprotein (MOG), a major target of central nervous system autoimmunity. We identified MOG-reactive autoantibodies in aged individuals and patients with MOG antibody-associated disease (MOGAD) and showed that the glycan at MOG N60 modulates autoantibody binding. Experimental autoimmune encephalomyelitis (EAE) recapitulated a subset of the age-associated glycosite changes, revealing shared glycosylation signatures between aging and autoimmune targeting of MOG. Together, these findings reveal site-specific N-glycosylation as both a marker of age and a regulator of molecular interactions.
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BibTeX
@misc{schoof2026atlas,
title = {{An atlas of the aging glycoproteome reveals how glycosylation modulates autoantibody binding in the brain}},
author = {Michael Schoof and Johannes Reitenbach and Kevin Abraham and George Tilton-Low and Danwei Wu and Seyone Chithrananda and Yarden Freund and Divya Channappa and Lauren E. Pepi and Jeffrey E. Dunn and Marius Wernig and May H. Han and Tal Iram and Erin H. Seeley and Ian H. Guldner and Carolyn R. Bertozzi and Tony Wyss-Coray},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.762617},
url = {https://www.biorxiv.org/content/10.64898/2026.10.28.762617v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - An atlas of the aging glycoproteome reveals how glycosylation modulates autoantibody binding in the brain
AU - Michael Schoof
AU - Johannes Reitenbach
AU - Kevin Abraham
AU - George Tilton-Low
AU - Danwei Wu
AU - Seyone Chithrananda
AU - Yarden Freund
AU - Divya Channappa
AU - Lauren E. Pepi
AU - Jeffrey E. Dunn
AU - Marius Wernig
AU - May H. Han
AU - Tal Iram
AU - Erin H. Seeley
AU - Ian H. Guldner
AU - Carolyn R. Bertozzi
AU - Tony Wyss-Coray
PY - 2026
DA - 2026/10/28
PB - bioRxiv
DO - 10.64898/2026.10.28.762617
UR - https://www.biorxiv.org/content/10.64898/2026.10.28.762617v1
AB - N-glycosylation generates substantial molecular diversity, yet how glycan composition varies throughout aging remains poorly understood. We mapped the N-glycoproteome of brain, liver, spleen, kidney, and plasma across nine ages spanning the mouse lifespan, identifying 80,618 unique N-glycopeptides at 9,211 glycosites on 4,391 glycoproteins, together with matched proteomic trajectories (glycoproteinatlas.org). Organ identity was the dominant determinant of glycan composition, but numerous glycosites nevertheless underwent remodeling with age. The brain showed a prominent age-associated increase in short paucimannose glycans, driven in part by the age-associated increase in the glycan-processing enzyme HEXB. In white matter, a hotspot for this change, aging increased the paucimannosylation of Myelin oligodendrocyte glycoprotein (MOG), a major target of central nervous system autoimmunity. We identified MOG-reactive autoantibodies in aged individuals and patients with MOG antibody-associated disease (MOGAD) and showed that the glycan at MOG N60 modulates autoantibody binding. Experimental autoimmune encephalomyelitis (EAE) recapitulated a subset of the age-associated glycosite changes, revealing shared glycosylation signatures between aging and autoimmune targeting of MOG. Together, these findings reveal site-specific N-glycosylation as both a marker of age and a regulator of molecular interactions.
SN - 2692-8205
ER -