ThePgb1locus controls glycogen aggregation in astrocytes of the aged hippocampus without impacting cognitive function

Abstract

Aging can be associated with the accumulation of hypobranched glycogen molecules (polyglucosan bodies, PGBs), particularly in astrocytes of the hippocampus. While PGBs have a detrimental effect on cognition in diseases such as adult polyglucosan body disease and Lafora disease, the underlying mechanism and clinical relevance of age-related PGB accumulation remains unknown. Here, we have investigated the genetic basis and functional impact of age-related PGB accumulation in 32 fully sequenced BXD-type strains of mice which exhibit a 400-fold variation in PGB burden in 16-18 month old females. We mapped a major locus controlling PGB density in the hippocampus to chromosome 1 at 72–75 Mb (linkage of 4.9 –logP), which we defined as thePgb1locus. To identify potentially causal gene variants withinPgb1, we generated extensive hippocampal transcriptome datasets and identified two strong candidate genes for which mRNA correlates with PGB density—Smarcal1andUsp37. In addition, bothSmarcal1andUsp37contain non-synonymous allele variations likely to impact protein function. A phenome-wide association analysis highlighted a trans-regulatory effect of thePgb1locus on expression ofHp1bp3, a gene known to play a role in age-related changes in learning and memory. To investigate the potential impact of PGBs on cognition, we performed conditioned fear memory testing on strains displaying varying degrees of PGB burden, and a phenome-wide association scan of ~12,000 traits. Importantly, we did not find any evidence suggesting a negative impact of PGB burden on cognitive capacity. Taken together, we have identified a major modifier locus controlling PGB burden in the hippocampus and shed light on the genetic architecture and clinical relevance of this strikingly heterogeneous hippocampal phenotype.