Journal Article

DZNE-2026-00220

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The Smarcal1-Usp37 locus modulates glycogen aggregation in astrocytes of the aged hippocampus.

Gómez-Pascual, A. ; Glikman, D. M. ; Ng, H. X. ; Tomkins, J. E. ; Lu, L. ; Xu, Y.DZNE* ; Ashbrook, D. G. ; Kaczorowski, C. ; Kempermann, G.DZNE* ; Killmar, J. ; Mozhui, K. ; Ohlenschläger, O. ; Aebersold, R. ; Ingram, D. K. ; Williams, E. G. ; Jucker, M.DZNE* ; Overall, R. W. ; Williams, R. W. ; de Bakker, D. E. M.

2026
Elsevier Maryland Heights, MO

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Please use a persistent id in citations: doi:10.1016/j.cels.2025.101488

Abstract: In aged humans and mice, hypobranched glycogen aggregates, known as polyglucosan bodies (PGBs), accumulate in hippocampal astrocytes. While PGBs are linked to cognitive decline in neurological diseases, they remain largely unstudied in the context of typical aging. We show that PGBs arise in autophagy-dysregulated astrocytes in the aged hippocampus, with substantial variation among 32 inbred BXD mouse strains. Genetic mapping through quantitative trait locus analysis identified a major locus (Pgb1) that modulates hippocampal PGB burden. Extensive transcriptomic and proteomic datasets were produced for the aged hippocampus of the BXD family to investigate the mechanism by which the Pgb1 locus modulates PGB burden. We identified that Pgb1 contains allelic Smarcal1 and Usp37 variants and influences PGB burden through trans-regulation of mRNA and protein expression levels, including abundance of glycogen-mobilizing factor PYGB. Furthermore, comprehensive phenome-wide association scans, transcriptomic analyses, and direct behavioral testing demonstrated that cognition remains intact despite age-related PGB burden. A record of this paper's transparent peer review process is included in the supplemental information.

Keyword(s): Animals (MeSH) ; Hippocampus: metabolism (MeSH) ; Glycogen: metabolism (MeSH) ; Mice (MeSH) ; Astrocytes: metabolism (MeSH) ; Aging: genetics (MeSH) ; Aging: metabolism (MeSH) ; Male (MeSH) ; Quantitative Trait Loci: genetics (MeSH) ; Mice, Inbred C57BL (MeSH) ; Humans (MeSH) ; Glucans (MeSH) ; astrocytes ; brain aging ; glycogen metabolism ; hippocampus ; polyglucosan bodies ; quantitative trait locus analysis ; system genetics ; Glycogen ; polyglucosan ; Glucans

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Contributing Institute(s):

1. Cell Biology of Neurological Diseases (AG Jucker)
2. Adult Neurogenesis (AG Kempermann)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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