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Reduced phosphatases and hyperphosphorylated glutamatergic receptors persist from early to late stages of prion disease
Rajic AJ, Ojeda-Juarez D, Sarkar D, Sumowski P, Flores S, Pourhamzeh M, Soldau K, Pizzo DP et al.. bioRxiv, 2026-10-16
Topic: Disease mechanisms in lab and animal studies
Synapse loss occurs early in prion disease, yet the intracellular signaling driving this dysregulation remains poorly understood. Evidence of neuronal hyperactivity was reported in humans with sporadic and familial CJD as well as in the early stages of prion disease in mice (strain 22L). Here we perform a time course study of prion-infected mice (strain RML) and show an increase in the immediate-early gene, Arc , suggesting this is a conserved response to prions. We also observed a persistent decrease in phosphatase abundance (PP1α and PP2B) in the cerebral cortex starting at the earliest timepoint (preclinical). At this stage, mGluR5 dimers and phosphorylated AMPA receptors were increased. By clinical disease onset, mGluR5 dimers declined and activity shifted toward NMDA receptor activation, marked by GluN2B hyperphosphorylation. Together, these findings suggest that early phosphatase reduction accompanies neuronal hyperactivity, and precedes substantial inflammation. Elucidating the mechanisms driving this early phosphatase loss and its role in neuronal hyperactivity may reveal novel therapeutic targets for prion disease. Significance statement Synapse loss and neuronal hyperactivity are early features of prion and Alzheimer’s disease (AD), yet the underlying molecular drivers remain poorly understood. In the current time course study, we reveal elevated levels of neuronal activity protein, Arc, at early, mid, and late timepoints of prion disease. Concurrently, we reveal a persistent and early reduction in key phosphatases (PP1α and PP2B). Additionally, we observed hyperphosphorylation of glutamatergic receptors starting from subclinical stages, before overt neuroinflammation or neuronal loss occur. Furthermore, we uncover a disease-stage-dependent transition from early AMPAR/mGluR5 alterations to late-stage NMDAR involvement. Understanding the mechanisms driving early phosphatase loss and neuronal hyperactivity could reveal novel therapeutic targets for prion disease.
Key findings
- Together, these findings suggest that early phosphatase reduction accompanies neuronal hyperactivity, and precedes substantial inflammation.
- Additionally, we observed hyperphosphorylation of glutamatergic receptors starting from subclinical stages, before overt neuroinflammation or neuronal loss occur.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 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 13 of the 62 points we could judge it on, which is 21 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 | 5 / 5 | 2026 — within 1 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 | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 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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APA 7th
Rajic, A. J., Ojeda-Juarez, D., Sarkar, D., Sumowski, P., Flores, S., Pourhamzeh, M., et al. (2026). Reduced phosphatases and hyperphosphorylated glutamatergic receptors persist from early to late stages of prion disease. bioRxiv. https://doi.org/10.64898/2026.10.14.751571
Vancouver
Rajic AJ, Ojeda-Juarez D, Sarkar D, Sumowski P, Flores S, Pourhamzeh M, et al. Reduced phosphatases and hyperphosphorylated glutamatergic receptors persist from early to late stages of prion disease. bioRxiv. 2026. doi:10.64898/2026.10.14.751571.
BibTeX
@article{rajic2026-c51e2b7b,
author = {Rajic, A. J. and Ojeda-Juarez, D. and Sarkar, D. and Sumowski, P. and Flores, S. and Pourhamzeh, M. and Soldau, K. and Pizzo, D. P. and others},
title = {{Reduced phosphatases and hyperphosphorylated glutamatergic receptors persist from early to late stages of prion disease}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.14.751571},
url = {https://doi.org/10.64898/2026.10.14.751571}
}