OSCR

Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs.

Overview

Authors: Nhat T T Le1, Robert C C Mercer1, Cheng Fang1, Aravind Sundaravadivelu1, Adam T Labadorf2, Weiwei Lin3, Julian Kwan1, Benjamin Blum1, Andrew Emili1, David A Harris1
ORCID iDs: Robert C C Mercer, Adam T Labadorf, David A Harris
  1. Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States of America
  2. Bioinformatics Program, Boston University, Boston, Massachusetts, United States of America
  3. Department of Pharmacology, Physiology and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States of America
Institutions: Boston University (United States)
Journal: PLoS pathogens, volume 22, issue 6, article e1014314
Dates: received 7 February 2026; accepted 26 May 2026; published online 18 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1371/journal.ppat.1014314 · PMID 42313800 · PMCID PMC13278431 · OpenAlex W7165134890
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), histology / microscopy (modality), mouse (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics, Machine learning, fMRI & imaging
MeSH: Neurons*, Prion Diseases*, Prions*, PrPSc Proteins*, Synapses*, Animals, Cells, Cultured, Dendritic Spines, Hippocampus, Mice, Proteomics, Receptors, N-Methyl-D-Aspartate, Signal Transduction, Synaptic Transmission (* major topic)
Topic: Prion Diseases and Protein Misfolding (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: NIA NIH HHS (R01 AG064932, RF1 AG061706); NINDS NIH HHS (R21 NS107755, R01 NS065244)
Citations: not cited yet (Europe PMC); 78 references in the paper

Abstract

Prion propagation, in which the cellular prion protein (PrPC) is conformationally converted into an infectious structure (PrPSc), has been extensively studied. However, the molecular mechanism responsible for the neurotoxicity of prions remains unclear. Synaptic loss is one of the earliest events in both in vivo and in vitro models of prion disease. We previously developed a neuronal cell culture model to analyze the mechanisms of prion-induced synaptic degeneration in a physiologically relevant setting. Using this system, we showed that exposure of hippocampal neurons to PrPSc engages a NMDAR/p38 mitogen-activated protein kinase (MAPK) signaling pathway that results in rapid, PrPC-dependent loss of synaptic transmission and retraction of dendritic spines. To comprehensively identify the components of this synaptotoxic signaling pathway, we measured changes in the phosphoproteome and transcriptome of hippocampal neurons exposed to PrPSc while they were undergoing the process of dendritic spine retraction. We then used these data as input into the L1000 and P100 databases of transcriptomic and proteomic drug signatures, leading to the discovery of 17 compounds that were able to prevent PrPSc-induced spine retraction. These compounds converged on three protein kinase targets: Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), and glycogen synthase kinase 3β (GSK3β). Using immunocytochemical staining, we confirmed that PrPSc treatment of hippocampal neurons induced phosphorylation of the three kinases and caused their rapid translocation to dendritic spines. Along with N-methyl-D-aspartate receptors (NMDARs) on the neuronal surface, which trigger an initial influx of Ca2+ in response to PrPSc, these kinases constitute key nodes in a signaling network that mediates prion synaptotoxicity. Taken together, our results provide new insights into the mechanisms of prion neurotoxicity, and they identify novel molecular targets and inhibitory compounds that can be utilized for therapy of prion diseases.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

Data Availability

All relevant data is contained within this manuscript, associated supplementary files, or in public repositories. Phosphoproteomic raw data are deposited in MassIVE under accession number MSV000100370. Transcriptomic data are deposited in GEO under accession number GSE325339.

Reproduced under the paper's license (CC BY), from the paper cited above.

Transcriptomic data availability

RNA-seq data are deposited in GEO under accession number GSE325339 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325339).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 14 MeSH terms, 2 funders, 77 references.

Cite

This paper

Le, N. T. T., Mercer, R. C. C., Fang, C., Sundaravadivelu, A., Labadorf, A. T., Lin, W., Kwan, J., Blum, B., Emili, A., & Harris, D. A. (2026). Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs. PLoS pathogens, 22(6), e1014314. https://doi.org/10.1371/journal.ppat.1014314

BibTeX

@article{le2026chemo,
author = {Le, Nhat T T and Mercer, Robert C C and Fang, Cheng and Sundaravadivelu, Aravind and Labadorf, Adam T and Lin, Weiwei and Kwan, Julian and Blum, Benjamin and Emili, Andrew and Harris, David A},
title = {{Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs}},
journal = {PLoS pathogens},
year = {2026},
month = jun,
volume = {22},
number = {6},
pages = {e1014314},
publisher = {PLOS},
issn = {1553-7366},
doi = {10.1371/journal.ppat.1014314},
url = {https://doi.org/10.1371/journal.ppat.1014314},
pmid = {42313800},
pmcid = {PMC13278431}
}

RIS

TY - JOUR
AU - Le, Nhat T T
AU - Mercer, Robert C C
AU - Fang, Cheng
AU - Sundaravadivelu, Aravind
AU - Labadorf, Adam T
AU - Lin, Weiwei
AU - Kwan, Julian
AU - Blum, Benjamin
AU - Emili, Andrew
AU - Harris, David A
TI - Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs
T2 - PLoS pathogens
J2 - PLoS Pathog
PY - 2026
DA - 2026/06/18
VL - 22
IS - 6
SP - e1014314
SN - 1553-7366
PB - PLOS
DO - 10.1371/journal.ppat.1014314
UR - https://doi.org/10.1371/journal.ppat.1014314
LA - en
ER -

CSL-JSON

{
"id": "10.1371/journal.ppat.1014314",
"type": "article-journal",
"title": "Chemo-omic pipeline enables discovery of prion synaptotoxic pathways and inhibitory drugs",
"container-title": "PLoS pathogens",
"author": [
{
"family": "Le",
"given": "Nhat T T"
},
{
"family": "Mercer",
"given": "Robert C C"
},
{
"family": "Fang",
"given": "Cheng"
},
{
"family": "Sundaravadivelu",
"given": "Aravind"
},
{
"family": "Labadorf",
"given": "Adam T"
},
{
"family": "Lin",
"given": "Weiwei"
},
{
"family": "Kwan",
"given": "Julian"
},
{
"family": "Blum",
"given": "Benjamin"
},
{
"family": "Emili",
"given": "Andrew"
},
{
"family": "Harris",
"given": "David A"
}
],
"container-title-short": "PLoS Pathog",
"volume": "22",
"issue": "6",
"page": "e1014314",
"DOI": "10.1371/journal.ppat.1014314",
"PMID": "42313800",
"PMCID": "PMC13278431",
"ISSN": "1553-7366",
"publisher": "PLOS",
"URL": "https://doi.org/10.1371/journal.ppat.1014314",
"language": "en",
"issued": {
"date-parts": [
[
2026,
6,
18
]
]
}
}

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1016/j.nbd.2026.107379 [code]
DYRK1A and Parkinson's disease, facts and hypotheses.
Journal: Neurobiology of disease
In common: cellular / molecular, 5 references
[2] doi:10.1016/j.stemcr.2026.102924
PrP<sup>C</sup>-facilitated cell signaling activates phospholipase Cɣ1 and triggers an Arc/Arg3.1 response in mouse and iPSC-derived human neurons.
Journal: Stem cell reports
In common: genetics / omics, other condition, mouse, 1 other category, 4 references
[3] doi:10.1186/s44477-026-00045-w [code]
Proteomic analysis of human chronic traumatic encephalopathy brain implicates proteasome and ribosome dysfunction in disease severity.
Journal: Molecular neurodegeneration advances
In common: genetics / omics, other condition, cellular / molecular, author Adam Labadorf
[4] doi:10.1038/s41467-026-73003-5 [code]
Gpnmb defines a phagocytic state of microglia linked to cell death in prion disease mouse model.
Journal: Nature communications
In common: other condition, mouse, cellular / molecular, 3 references
[5] doi:10.1093/nar/gkag287 [code]
Divalent siRNA for prion disease.
Journal: Nucleic acids research
In common: other condition, mouse, 3 references
[6] doi:10.1186/s13293-026-00930-9
Early, sex-dependent and progressive proteomic imbalance in the amygdala during Alzheimer´s disease continuum.
Journal: Biology of sex differences
In common: histology / microscopy, genetics / omics, 3 references
[7] doi:10.1038/s41598-026-51816-0
Altered molecular signaling pathways in the hippocampus of rhesus monkeys following chronic alcohol use.
Journal: Scientific reports
In common: genetics / omics, other condition, cellular / molecular, 3 references
[8] doi:10.1016/j.isci.2026.116336 [code]
Transcriptomic signatures of synaptic loss in Alzheimer's disease.
Journal: iScience
In common: genetics / omics, cellular / molecular, 3 references
[9] doi:10.1016/j.stemcr.2026.102977 [code]
Integrative analysis of drug-gene signatures in human pluripotent stem cells reveals prazosin as a novel SQSTM1 regulator for ALS therapeutics.
Journal: Stem cell reports
In common: genetics / omics, other condition, cellular / molecular, 2 references
[10] doi:10.1371/journal.ppat.1014263 [code]
PrP turnover in vivo and the time to effect of prion disease therapeutics.
Journal: PLoS pathogens
In common: other condition, mouse, 2 references

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion, reproductions, activity

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.