JAX BXD Hippocampal Proteome (Jul23) Log2

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Polyglucosan bodies (PGBs) are intracellular aggregates of misfolded glycogen molecules accumulating in astrocytes of the central nervous system during disease and aging. While PGBs are extensively studied within the context of adult polyglucosan body disease and Lafora disease, the genetic architecture and clinical relevance of PGBs during aging remains largely undescribed. Here, we quantified PGBs in the hippocampus of BXD mice family, generated by crossing C57BL/6J with DBA/2J strains with high and low age-related burden, respectively. We discovered a highly heritable 500-fold variation in PGB burden between strains in 18-month old females. Variation in PGB densities was mapped using genome-wide maker maps and a linear mixed model (GEMMA), which revealed a novel modifier locus on chromosome 1 (72-75 Mb). This PGB associated locus (Pgb1) contains 47 protein-coding genes. To assess whether expression of these 47 candidate genes correlate with PGB burden, we generated hippocampal transcriptome and proteome data for animals between 6 and 25 months of age. For each candidate, we assessed aged-related expression in the hippocampus, expression-correlations with PGB density as well as the occurrence of non-synonymous allele variations. We identified two candidates that could affect variation in PGB burden through both expression level changes and via altering protein function due to non-synonymous allele variation, Smarcal1 and Usp37. In addition, phenome-wide association analysis with aged transcriptome and proteome data identified that the Pgb1 locus modulates expression of Hp1bp3, a gene known to play a role in age-related changes in learning and memory. However, we did not find compelling behavioral evidence linking PGB burden with cognitive decline. Taken together, we identified a novel modifier locus controlling PGB burden in the hippocampus and shed light on the genetic architecture and clinical relevance of this strikingly heterogeneous hippocampal phenotype.

About tissue

All mice were obtained as juveniles from The Jackson Laboratory and aged at the Gerontology Research Center, NIA between 1997 and 1999 by one of us (see Jucker et al., 2000 for details). Approximately 10 females of each of a total of 61 independent strains of mice were studied. This includes three parental strains of the BXD and AXB/BXA families of recombinant inbred strains, C57BL/6J, DBA/2J, and A/J, as well as 30 BXD strains and 28 fully independent AXB/BXA strains. All BXD cases used in the present analysis were aged to 18 months prior to sacrifice. Data and maps of variation in hippocampal PGB density in the AXB/BXA family are not considered in detail in this study but are available in GeneNetwork as AXB_10100).

Animals were euthanized by pentobarbital overdose and perfused transcardially with 0.1 M phosphate-buffered saline (PBS) at pH 7.4, followed by 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4, at room temperature. Brains were post-fixed overnight and placed in 30% sucrose in PBS for two days at 4 °C. Brains were frozen in 2-methylbutane and stored at –70°C and eventually sectioned at 25 microns for histological staining of polyglucosan bodies as described below.

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