UC San Diego

Although progressive supranuclear palsy (PSP) is a sporadic neurodegenerative disease, a genome-wide association study identified candidate genes as risk factors. One of these genes EIF2AK3 encodes protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK), one of three stress sensors, alongside inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6), in the endoplasmic reticulum (ER). Collectively known as the unfolded protein response (UPR), these sensors attempt to maintain protein homeostasis before resorting to programmed cell death. IRE1 splices X-box binding protein 1 (XBP1) mRNAs to form transcription factors that upregulate UPR components. ATF6 is modified to form transcription factors that upregulate ER chaperones like binding immunoglobulin protein (BiP). PERK phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2), attenuating translation with exceptions of activating transcription factor 4 (ATF4) mRNAs. ATF4 then upregulates CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), a proapoptotic protein. Four single nucleotide polymorphisms (SNPs) in PERK are in linkage disequilibrium. The haplotype B variant, with minor alleles for all four, confers deleterious effects. Using patient fibroblasts, this study aimed to characterize the haplotype’s effects on PSP pathology and UPR activation. Haplotype B heterozygous fibroblasts displayed heightened sensitivity to ER stress and excessive cell death. Haplotype B fibroblasts had decreased ER stress sensitivity and insignificant amounts of cell death. Basal levels of eIF2 phosphorylation for the two genotypes were comparable. Haplotype B did not affect IRE1 activity and changes in BiP expression, an indicator of ATF6 activation, were drug-dependent only for haplotype B heterozygous fibroblasts.