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Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction
Reineke LC, Zhu PJ, Dalwadi U, Dooling SW, Liu Y, Wang I, Young-Baird S, Okoh J et al.. bioRxiv, 2025-03-02
Topic: Genetics and APOE
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 R658C 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 Ppp1r15b R658C 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.
Key findings
- Here, we investigated how persistent ISR activation impacts cognitive performance, primarily focusing on a PPP1R15B R658C 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 Ppp1r15b R658C mice are directly due to ISR activation.
- 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.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 19 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 12 of the 62 points we could judge it on, which is 19 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 12 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 12 of the 62 points we could judge it on is 19 out of 100. |
| Total | 19 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Reineke, L. C., Zhu, P. J., Dalwadi, U., Dooling, S. W., Liu, Y., Wang, I., et al. (2025). Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction. bioRxiv. https://doi.org/10.1101/2025.02.28.640897
Vancouver
Reineke LC, Zhu PJ, Dalwadi U, Dooling SW, Liu Y, Wang I, et al. Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction. bioRxiv. 2025. doi:10.1101/2025.02.28.640897.
BibTeX
@article{reineke2025-81e24ed0,
author = {Reineke, L. C. and Zhu, P. J. and Dalwadi, U. and Dooling, S. W. and Liu, Y. and Wang, I. and Young-Baird, S. and Okoh, J. and others},
title = {{Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction}},
journal = {bioRxiv},
year = {2025},
doi = {10.1101/2025.02.28.640897},
url = {https://doi.org/10.1101/2025.02.28.640897}
}
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