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

Schoof, M.; Reitenbach, J.; Abraham, K.; Tilton-Low, G.; Wu, D.; Chithrananda, S.; Freund, Y.; Channappa, D.; Pepi, L. E.; Dunn, J. E.; Wernig, M.; Han, M. H.; Iram, T.; Seeley, E. H.; Guldner, I. H.; Bertozzi, C. R.; Wyss-Coray, T.

doi:10.64898/2026.10.28.762617

bioRxiv · 10.64898/2026.10.28.762617

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

Schoof, M.·Reitenbach, J.·Abraham, K.·Tilton-Low, G.·Wu, D.·Chithrananda, S.·Freund, Y.·Channappa, D.·Pepi, L. E.·Dunn, J. E.·Wernig, M.·Han, M. H.·Iram, T.·Seeley, E. H.·Guldner, I. H.·Bertozzi, C. R.·Wyss-Coray, T.

View original source ↗Export metadata ↓

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.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Schoof, M., Reitenbach, J., Abraham, K., Tilton-Low, G., Wu, D., Chithrananda, S., Freund, Y., Channappa, D., Pepi, L. E., Dunn, J. E., Wernig, M., Han, M. H., Iram, T., Seeley, E. H., Guldner, I. H., Bertozzi, C. R., Wyss-Coray, T.. 2026-10-31. An atlas of the aging glycoproteome reveals how glycosylation modulates autoantibody binding in the brain. https://doi.org/10.64898/2026.10.28.762617

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Chronic unpredictable stress induces negative cognitive bias in rats with sex-specific changes in neurogenesis and functional connectivity

Background: Females are more likely to be diagnosed with major depressive disorder (MDD) than males. Cognitive symptoms of MDD include negative cognitive bias, the perception of ambiguous situations as negative, which predicts MDD episode onset and severity. MDD is associated with changes to functional connectivity between regions involved in cognition, emotion, attention, and memory. Methods: Here we examined the impact of chronic unpredictable stress (CUS) on negative cognitive bias in male (n=18) and female (n=22) Sprague-Dawley rats. We assessed hippocampal neurogenesis and c-Fos expression in response to an ambiguous context across 15 regions of the frontal cortex, amygdala, nucleus accumbens, and hippocampus, including in newborn dentate gyrus (DG) neurons, to examine functional connectivity during cognitive bias testing. We conducted a graph-based network analysis and constructed linear models to predict freezing in the ambiguous context based on regional activation. Results: CUS-exposed rats froze more to the ambiguous context than non-CUS-exposed rats, regardless of sex. CUS decreased neurogenesis in the ventral DG of both sexes, and increased activation of new neurons in the dorsal DG of males only. In response to the ambiguous context, CUS males had an increase in c-Fos expression in the amygdala. CUS produced extensive, sex-specific network reorganization, decreasing global network efficiency in males but not in females. Freezing in the ambiguous context was predicted by activation of new neurons in combination with the ventral CA1 in opposing directions across sex. Conclusions: These findings suggest that sex-specific pathways drive the expression of CUS-induced negative cognitive bias, underscoring the necessity of sex-stratified preclinical and clinical research on negative cognitive bias in depression.

neuroscience↗

bioRxiv2026

Multimodal profiling and intersectional genetics reveal CA1 border inhibitory neuron diversity and postnatal emergence of retrosplenial connectivity

Inhibitory neurons (INs) at the stratum radiatum/stratum lacunosum-moleculare border of hippocampal CA1 comprise diverse populations, including long-range-projecting neurons that innervate the retrosplenial cortex (RSCtx). However, their molecular organization and developmental connectivity remain poorly understood. Here, we combine multimodal transcriptomic profiling, intersectional genetics, and retrograde tracing to characterize CA1 border INs. We identified two major caudal ganglionic eminence-derived, Cxcl14-enriched populations distinguished by Syt6/Cck-related and Ntng1-expressing transcriptional profiles. We then generated a Cxcl14-Cre mouse line that, when combined with an IN-specific viral enhancer, provides genetic access to CA1 border INs. Retrograde labeling established that CA1 INs projecting to the RSCtx belong to the Ntng1-expressing population, and that this long-range projection emerges during postnatal mouse development, between postnatal days 3 and 5. Finally, analysis of genes encoding cell-surface proteins, key regulators of connectivity, revealed distinct expression profiles in RSCtx-projecting and SYT6-positive INs. Together, these findings establish a molecular and developmental framework for CA1 border IN diversity and provide a genetic strategy for investigating the assembly and function of these inhibitory circuits.

neuroscience↗

bioRxiv2026

Fixel-wise Differences in White Matter Fiber-bundle Cross-section identified in Children who Stutter

Developmental stuttering has been repeatedly linked to decreased white matter integrity and structural connectivity differences in major white matter tracts. Prior diffusion-weighted MRI studies reporting such white matter structural differences involved voxel-averaged tensor measures (e.g., fractional anisotropy (FA)). A well-acknowledged limitation of this approach, however, has been that it cannot resolve distinct fiber populations within crossing-fiber regions. Fixel-based analysis addresses this limitation by quantifying individual fiber populations within a voxel and providing complementary measures of fiber density (FD), fiber-bundle cross-section (FC), and their combined measure (FDC).Here we applied Fixel-based analysis to diffusion MRI data from 171 children aged 3 - 13 years, including 84 children who stutter and 87 typically developing controls, to test whether white-matter differences associated with developmental stuttering were expressed as differences in FD, FC, and FDC and whether these measures show group-specific age-related patterns. We evaluated this at both the whole-brain level and within a priori white-matter tracts.FC, but not FD or FDC, showed significant Group and Group by Age effects, indicating that white-matter differences were primarily expressed in fiber-bundle macrostructure. Tract-of-interest analyses identified developmental differences in bilateral arcuate fasciculus FC that remained significant across tracts, with controls showing greater age-related increases in FC than children who stutter. Additional FC differences were observed across corticospinal and thalamocortical pathways, although these tract-wise effects were less robust to across-tract correction. These findings suggest that white-matter differences in developmental stuttering are prominently expressed in fiber-bundle macrostructure rather than fiber density and highlight divergent development of bilateral arcuate pathways. FBA provides fiber-specific information that complements conventional tensor-based diffusion measures and may improve characterization of white-matter development in childhood stuttering.

neuroscience↗