ER Stress Activity and Neurodegeneration in Human PERK cDNA Knock-in Mice
Tauopathies are characterized by the progressive accumulation of hyperphosphorylated protein tau, which leads to endoplasmic reticulum (ER) stress in the cell. With severe and prolonged ER stress, a pro-apoptotic pathway called the PERK pathway is triggered as part of the unfolded protein response. Genome-wide association studies (GWAS) revealed that the coding region of the gene that encodes PERK, EIF2AK3, shows three single nucleotide polyorphisms (SNPs) in linkage disequilibrium. Of the study population, 30% had a haplotype that is suspected to increase susceptibility to tauopathy. This study aimed to identify if ER stress and neurodegeneration was affected in human PERK cDNA knock-in mice with the risk variant haplotype (hPERKB) relative to the haplotype possessed by 70% of the GWAS population (hPERKA). The study used ten hPERKA mice and nine hPERKB mice and protein was isolated from the right hemisphere of mouse brain. The ER stress markers eIF2α, phospho-eIF2α, PERK, phospho-PERK, ATF4, GADD34 and neurodegeneration markers, tau, phospho-tau, cPARP, were quantified using WES™ automated western blotting. Analysis revealed no statistically significant differences between hPERK A and hPERKB for any of the proteins measured (p>0.05). The data suggests that human PERK cDNA knock-in is likely insufficient to cause significant ER stress in the mouse model, and crossing hPERK mice with mouse model of hyperphosphorylated tau may be necessary to understand if the SNPs induced in hPERKB increase susceptibility to tauopathy.