BackgroundA major challenge in the field of tauopathies, such as progressive supranuclear palsy (PSP) is identification of effective therapeutic targets. PKR‐like endoplasmic reticulum (ER) kinase haplotype A (PERK‐A) adapts cells undergoing ER stress. PERK haplotype B (PERK‐B) does not resolve ER stress effectively and increases the risk for PSP. The mechanism by which PERK‐A and ‐B confer distinct outcomes remains unknown. The overall hypothesis is that PERK‐B promotes maladaptive response that increases tauopathy outcomes.MethodsWe developed new inducible cell lines, unfolded protein response sensors, and PERK plasmids (‐A, ‐B, and an inactive variant, ‐K). We performed molecular biology approaches in vitro including co‐expression, co‐immunoprecipitation assays, and RNAseq.ResultsWe found that unlike PERK‐A, PERK‐B was not an effective modulator of pathological tau species. The transcriptome and translatome of PERK‐A and ‐B are distinct. Surprisingly, the PERK‐A translatome has pro‐survival factors.ConclusionPERK‐A confers benefits in tauopathy. The PERK‐A translatome is replete with novel therapeutic targets. PERK‐B data offer novel insights into the pathogenesis and progression of PSP, which may be linked to other tauopathies.