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TitleHarnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateMar 2, 2025
PubMed AbstractThe integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts ...The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts cognitive performance, primarily focusing on a PPP1R15B genetic variant associated with intellectual disability. By generating a novel mouse model that mimics this human condition, we revealed that this variant destabilizes the PPP1R15B•PP1 phosphatase complex, resulting in chronic ISR activation, impaired protein synthesis, and deficits in long-term memory. Importantly, we found that the cognitive and synaptic deficits in mice are directly due to ISR activation. Leveraging insights from evolutionary biology, we characterized DP71L, a viral orthologue of PPP1R15B, through detailed molecular and structural analyses, uncovering its mechanism of action as a potent pan-ISR inhibitor. Remarkably, we found that DP71L not only buffers cognitive decline associated with a wide array of conditions-including Down syndrome, Alzheimer's disease and aging-but also enhances long-term synaptic plasticity and memory in healthy mice. These findings highlight the promise of utilizing evolutionary insight to inform innovative therapeutic strategies.
External linksbioRxiv / PubMed:40568171 / PubMed Central
MethodsEM (single particle)
Resolution3.03 - 3.8 Å
Structure data

EMDB-49124: Consensus reconstruction of the Dp71L-PP1A-eIF2alpha holophosphatase stabilized by G-actin/DNAseI
Method: EM (single particle) / Resolution: 3.03 Å

EMDB-49162: Focused refinement of G-actin within the Dp71L-PP1A-eIF2alpha-DNAseI-G-actin complex
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-49163: Focused refinement of the Dp71L-eIF2alpha-PP1A subcomplex within the holo-phosphatase complex.
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-49164: Focused refinement of DNAseI within the Dp71L-eIF2alpha-PP1A-Gactin-DNAseI holo-phosphatase complex.
Method: EM (single particle) / Resolution: 3.8 Å

49223

9nb9

EMDB-49223, PDB-9nb9:
Viral protein DP71L in complex with phosphorylated eIF2alpha (NTD) and protein phosphatase 1A (D64A), stabilized by G-actin/DNAseI
Method: EM (single particle) / Resolution: 3.03 Å

Chemicals

ChemComp-MN:
Unknown entry

ChemComp-CA:
Unknown entry

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

Source
  • homo sapiens (human)
  • african swine fever virus
  • oryctolagus cuniculus (rabbit)
  • bos taurus (domestic cattle)
KeywordsTRANSLATION / Phosphatase / complex / ISR

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