Tauopathy-Associated PERK Alleles Increase Neuronal Vulnerability to ER Stress via loss of function Shauna H. Yuan1,5*, Nobuhiko Hiramatsu2,3, Qing Liu1, Xuehan Victoria Sun3, David Lenh1, Priscilla Chan3, Karen Chiang1,3, Edward H. Koo1,6, Aimee S. Kao4, Irene S. Litvan1, Jonathan H. Lin3,5* 1Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093; 2Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Ishikawa, 920-0293, JAPAN; 3Department of Pathology, University of California, San Diego, La Jolla, CA 92093; 4Department of Neurology, University of California, San Francisco, San Francisco, CA 94158; 5VA San Diego Healthcare System, San Diego, CA 9216; 6Departments of Medicine and Physiology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore 117549 *Co-Corresponding authors
Tauopathies are neurodegenerative diseases defined by misfolded hyperphosphorylated tau protein deposits as neurofibrillary tangles (NFT) in the brain. Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases including tauopathies; however the mechanism is still not clear. EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), also known as PERK (protein kinase R-like endoplasmic reticulum kinase), was identified as a genetic risk factor in tauopathies and Alzheimer's Disease (AD) in genome-wide association study (GWAS). The risk single nucleotide polymorphism (SNP) identified in GWAS, rs7571971, is in the same haplotype (haplotype B), which includes three exonic SNPs: S136C, R166G, and S704A. We hypothesized that the SNPs in haplotype B altered normal PERK function; therefore, increased the risk for neurodegeneration. We found that tauopathy-associated PERK alleles showed reduced activity in response to ER stress due to decreased kinase activity and increased instability. The human patient induced pluripotent stem cells (iPSC) derived neurons carrying PERK risk alleles were highly vulnerable to ER stress-induced injury and were associated with increased tau and p-tau level. Furthermore, iPSC derived neurons carrying normal PERK alleles were susceptible to ER stress and tau protein pathology when treated with PERK inhibitor. Our results suggest that impaired PERK activity sensitizes neurons to ER stress and may underlie the increased risk for neurodegenerative tauopathies. These findings may have implications on designing personalized therapeutics and clinical trials in patients with tauopathy.
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