Overexpression of the Hspa13 ( Stch ) gene reduces prion disease incubation time in mice

Abstract

Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. To test this hypothesis, we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins, which have been previously implicated in prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period, we tested two overexpressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/Rocky Mountain Laboratory (RML) prion inoculation, shows a 4% reduction in incubation time. Furthermore, a transgenic model with eightfold overexpression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16, 15, and 7% following infection with Chandler/RML, ME7, and MRC2 prion strains, respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as prion disease.

Sod1 Deficiency Reduces Incubation Time in Mouse Models of Prion Disease

“…The only phenotype associated with these mice is female sterility in homozygote knockouts [27]. We inoculated mice intracerebrally with two different mouse-adapted scrapie prion strains, Chandler/RML and ME7, and a mouse adapted BSE prion strain, MRC2 (BSE passaged in Prnp a mice) [28], [34]. In Sod1 −/− mice a significant decrease in incubation time was seen for all three prion strains as compared to Sod1 +/+ controls (Figure 2 and Table S2).…”

“…The Chandler/RML (I9900), ME7 (I9459) and MRC2 (I9468) prion strains were sourced and prepared as previously described [22], [28]. Mice were anaesthetized with isofluorane/O 2 and inoculated intra-cerebrally into the right parietal lobe with 30 µl of inocula as previously described [15].…”

“…For detection of Sod1, samples were prepared as above but without proteinase K digestion and detected with a rabbit polyclonal antibody (0.5 ug/ml) (Abcam). Anti-β-actin mouse monoclonal antibody (0.05 ug/ml) (Sigma) was used as an internal control as previously described [28].…”

The Dynamic Duo of Small Heat Proteins and IFs Maintain Cell Homeostasis, Resist Cellular Stress and Enable Evolution in Cells and Tissues

“…In mice the absence of CRYAB in combination with another sHSP, HSPB2, exacerbates the behavioral changes in an Alzheimer model (Ojha et al 2011 ). In contrast the overexpression of a HSP70 class chaperone, Hspa13, accelerated prion-mediated disease in mice (Grizenkova et al 2012 ). These studies support the argument that αB-crystallin, like HSP90, has capacitor-like activity with respect to genetic traits Proteostasis and Cell Cycle Control The overexpression of αB-crystallin can reverse the morbidity in mice caused by GFAP (Hagemann et al 2009 ) and in cellular models this is likely due to increased proteasomal activity .…”

Genetics of prion diseases

“…We have taken the alternative approach of looking for differential expression between inbred lines of mice with different incubation times. We used uninfected mice and to enrich for relevant genes we looked for a correlation between expression level and incubation time across five lines of mice [35]. Five potential candidates were identified including Hspa13 ( Stch ), a member of the Hsp70 family of ATPase heat shock proteins.…”