Progressive Supranuclear Palsy PERK haplotype B selectively translates DLX1 promoting tau toxicity.

The unfolded protein response (UPR) sensor PERK exists in haplotypes A and B. PERK-B confers increased risk for tauopathies like progressive supranuclear palsy (PSP), but the mechanisms distinguishing its function from PERK-A and contributing to its association with tauopathy remain unknown. Here, we developed a controlled cellular model for a pair-wise comparison of the two PERK haplotypes, finding their UPR functions nearly indistinguishable. Puromycin-based proteomics highlighted a subset of mRNA translation events was permissible under the PERK-B, but not the PERK-A, dependent UPR. One of the targets that escaped PERK-B suppression was the transcription factor DLX1, which is genetically linked to PSP risk. We found that DLX1 solubility shifted to a detergent-insoluble fraction in human brain tissue from male and female PSP donors. Furthermore, silencing the fly homolog of DLX1 was sufficient to decrease tau-induced toxicity, in vivo. Our results detail the haplotype-specific PERK-B/DLX-1 pathway as a novel driver of tau pathology in cells, flies, and likely human brain, revealing new insights into PSP pathogenesis and potential therapeutic targets.Significance Statement Progressive supranuclear palsy (PSP) is a devastating neurodegenerative tauopathy with no effective treatments. This study identifies how a genetic risk factor for PSP, the PERK-B haplotype, contributes to disease pathogenesis. Using novel cellular and animal models, we demonstrate that PERK-B selectively promotes translation of DLX1, a transcription factor genetically linked to PSP. Importantly, DLX1 accumulates in a detergent insoluble fraction in human PSP brains, and reducing DLX1 mitigates tau-induced toxicity in vivo. These findings reveal a previously unknown PERK-B/DLX1 pathway that drives tauopathy. By elucidating this mechanism, our work opens new avenues for therapeutic intervention in PSP and related tauopathies. More broadly, this research highlights the importance of haplotype-specific effects and selective translational regulation in neurodegenerative disease, with implications for personalized medicine approaches.