The Smarcal1-Usp37 locus modulates glycogen aggregation in astrocytes of the aged hippocampus.

Polyglucosan bodies (PGBs) accumulate in autophagy-dysregulated astrocytes in the aged hippocampus with substantial variation among inbred mouse strains.

• PGB accumulation was studied across 32 inbred BXD mouse strains
• PGBs are hypobranched glycogen aggregates that accumulate in hippocampal astrocytes during aging in both humans and mice
• PGB formation was linked to autophagy dysregulation in astrocytes of the aged hippocampus
• Substantial inter-strain variation in PGB burden was observed across the BXD family

Quantitative trait locus (QTL) analysis identified a major locus, designated Pgb1, that modulates hippocampal PGB burden.

• The locus was identified through genetic mapping using the BXD family of 32 inbred strains
• The locus was named Pgb1 (polyglucosan body 1)
• Pgb1 was identified as the primary genetic modulator of hippocampal PGB burden in aged mice
• The QTL analysis leveraged the genetic diversity of the BXD recombinant inbred panel

The Pgb1 locus contains allelic variants in Smarcal1 and Usp37 genes that influence PGB burden.

• Both Smarcal1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1) and Usp37 (ubiquitin-specific peptidase 37) harbor allelic variants within the Pgb1 locus
• These variants were identified through extensive transcriptomic and proteomic datasets generated for the aged hippocampus of the BXD family
• The Pgb1 locus modulates PGB burden through trans-regulation of mRNA and protein expression levels

The Pgb1 locus influences PGB burden through trans-regulation of expression levels including abundance of the glycogen-mobilizing factor PYGB.

• PYGB (brain glycogen phosphorylase) was identified as a trans-regulated target of the Pgb1 locus
• Both mRNA and protein expression levels were affected by trans-regulation from the Pgb1 locus
• Extensive transcriptomic and proteomic datasets of the aged hippocampus were produced to investigate the mechanism
• PYGB is described as a 'glycogen-mobilizing factor,' implicating glycogen metabolism dysregulation in PGB accumulation

Cognition remains intact despite age-related PGB burden in the hippocampus.

• Comprehensive phenome-wide association scans were performed to assess the relationship between PGB burden and cognitive outcomes
• Transcriptomic analyses were conducted alongside direct behavioral testing
• Direct behavioral testing demonstrated that cognition was not impaired despite age-related PGB accumulation
• This finding distinguishes typical aging-associated PGBs from the pathological PGBs associated with neurological diseases and cognitive decline

PGBs are linked to cognitive decline in neurological diseases but remain largely unstudied in the context of typical aging.

• PGBs had previously been associated with cognitive decline in neurological disease contexts
• The study represents an investigation into PGBs specifically in the context of typical aging rather than disease
• PGBs arise in aged humans and mice in the hippocampus