| Title: |
Progressive Supranuclear Palsy PERK Haplotype B Selectively Translates DLX1 Promoting Tau Toxicity. |
| Authors: |
Lessard, Christian B.; Rubio, Diego Rubio; Tolton, Samantha; Criado-Marrero, Marangelie; Ravi, Sakthivel; Garza, Tristyn N.; Koren, John; Philips, Jennifer; Bagchi, Pritha; McFarland, Karen; Chhangani, Deepak; Golde, Todd E.; Giasson, Benoit I.; Lewis, Jada; Chakrabarty, Paramita; LaVoie, Matthew J.; Borchelt, David R.; Seyfried, Nicholas T.; Prokop, Stefan; Rincon-Limas, Diego E. |
| Source: |
Journal of Neuroscience; 4/1/2026, Vol. 46 Issue 13, p1-10, 10p |
| Subject Terms: |
HAPLOTYPES; PROGRESSIVE supranuclear palsy; UNFOLDED protein response; HOMEOBOX proteins; TAU proteins; NEURODEGENERATION; TAUOPATHIES; PROTEOMICS |
| Abstract: |
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 that was permissible under the PERK-B–dependent, 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 the 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 the human brain, revealing new insights into PSP pathogenesis and potential therapeutic targets. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |