Progressive Supranuclear Palsy PERK haplotype B selectively translates DLX1 promoting tau toxicity
Lessard, C. B.; Rubio-Rubio, D.; Tolton, S.; Criado-Marrero, M.; Ravi, S.; Garza, T. N.; Koren, J.; Phillips, J.; Bagchi, P.; McFarland, K. N.; Chhangani, D.; Golde, T.; Giasson, B. I.; Lewis, J.; Chakrabarty, P.; LaVoie, M. J.; Borchelt, D. R.; Seyfried, N. T.; Prokop, S.; Rincon-Limas, D. E.; Abisambra, J.
Show abstract
The unfolded protein response (UPR) sensor PERK exists in two haplotypes termed A and B. PERK-B uniquely 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 tau pathology are not known. Here, we developed a controlled cellular model for a pair-wise comparison of the two PERK haplotypes, finding their UPR functions nearly indistinguishable. However, a careful examination employing puromycin-based proteomics revealed that a subset of mRNA translation events were permissible under PERK-B, but not PERK-A, dependent UPR. Critically, one of the targets that escaped PERK-B suppression was the transcription factor DLX1, which has been genetically linked to PSP risk. Here, we found a shift in the solubility of DLX1 in human PSP brain tissue, and report that silencing of DLX-1 reduced the aggregation of tau in mammalian cells. Furthermore, silencing of 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.
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