TY  - JOUR
AU  - Gómez-Pascual, Alicia
AU  - Glikman, Dow M
AU  - Ng, Hui Xin
AU  - Tomkins, James E
AU  - Lu, Lu
AU  - Xu, Ying
AU  - Ashbrook, David G
AU  - Kaczorowski, Catherine
AU  - Kempermann, Gerd
AU  - Killmar, John
AU  - Mozhui, Khyobeni
AU  - Ohlenschläger, Oliver
AU  - Aebersold, Rudolf
AU  - Ingram, Donald K
AU  - Williams, Evan G
AU  - Jucker, Mathias
AU  - Overall, Rupert W
AU  - Williams, Robert W
AU  - de Bakker, Dennis E M
TI  - The Smarcal1-Usp37 locus modulates glycogen aggregation in astrocytes of the aged hippocampus.
JO  - Cell systems
VL  - 17
IS  - 2
SN  - 2405-4712
CY  - Maryland Heights, MO
PB  - Elsevier
M1  - DZNE-2026-00220
SP  - 101488
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Hippocampus: metabolism
KW  - Glycogen: metabolism
KW  - Mice
KW  - Astrocytes: metabolism
KW  - Aging: genetics
KW  - Aging: metabolism
KW  - Male
KW  - Quantitative Trait Loci: genetics
KW  - Mice, Inbred C57BL
KW  - Humans
KW  - Glucans
KW  - astrocytes (Other)
KW  - brain aging (Other)
KW  - glycogen metabolism (Other)
KW  - hippocampus (Other)
KW  - polyglucosan bodies (Other)
KW  - quantitative trait locus analysis (Other)
KW  - system genetics (Other)
KW  - Glycogen (NLM Chemicals)
KW  - polyglucosan (NLM Chemicals)
KW  - Glucans (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41633365
DO  - DOI:10.1016/j.cels.2025.101488
UR  - https://pub.dzne.de/record/285354
ER  -