Evidence map›Paper›PMID 42425332›Full record

ArticleMolecular and cellular neurosciences2026

Phenotypic screening for small molecules that lower PrP in cultured cells.

Jeannine A Frei, Andrew G Reidenbach, Leo M H Xu, Raja Mohan Gopalakrishnan, Dominick Casalana, Daniel A Sprague, Mark-Anthony Bray, Amy Q Wang, Vanessa Laversenne, Brian Erickson and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular and cellular neurosciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

15 authors.

Jeannine A FreiProgram in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Andrew G ReidenbachProgram in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Leo M H XuProgram in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Raja Mohan GopalakrishnanProgram in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Dominick CasalanaFacilitated Access to Screening Technologies (FAST) Lab, Novartis Institutes for Biomedical Research, Cambridge, MA, 02139, USA.
Daniel A SpragueProgram in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Mark-Anthony BrayFacilitated Access to Screening Technologies (FAST) Lab, Novartis Institutes for Biomedical Research, Cambridge, MA, 02139, USA.
Amy Q WangEarly Translation Branch, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Rockville, MD, 20850, USA.
Vanessa LaversenneProgram in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Brian EricksonIQ Proteomics, Framingham, MA, 01702, USA.
Craig BraunIQ Proteomics, Framingham, MA, 01702, USA.
Mckenzie HallEarly Translation Branch, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Rockville, MD, 20850, USA.
Douglas AuldFacilitated Access to Screening Technologies (FAST) Lab, Novartis Institutes for Biomedical Research, Cambridge, MA, 02139, USA.
Eric Vallabh MinikelProgram in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA, 02115, USA; Prion Alliance, Cambridge, MA, 02139, USA. Electronic address: eminikel@broadinstitute.org.
Sonia M VallabhProgram in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA, 02115, USA; Prion Alliance, Cambridge, MA, 02139, USA. Electronic address: svallabh@broadinstitute.org.

Funding

Mechanism of Action of Prion Protein-Lowering Small MoleculesR01NS131663 · NINDS · BROAD INSTITUTE, INC. · PI Sonia Minikel Vallabh · 2023 to 2026
$1.6M
NINDS NIH HHS R01 NS131663
6 · The paper itself

Abstract

Prion protein (PrP) lowering is a validated therapeutic hypothesis in prion disease. To identify small molecules that reduce PrP levels, we performed phenotypic screening in cultured cells. To prioritize PrP specificity in our primary screen, we generated mouse N2a cells stably expressing GFP and used high content imaging analysis to select compounds that lowered PrP without affecting GFP signal or cell viability. Screening a curated library of 3492 compounds with annotated mechanisms of action identified two small molecules, EYH (PubChem CID: 71678945) and LCZ (PubChem CID: 24970350), that selectively and dose-dependently lowered PrP. Proteomics on whole cell lysates identified PrP as the #1 or #2 most potently downregulated out of 8722 proteins detected. Both compounds minimally affected Prnp mRNA, reduced expression of exogenously transfected PrP, and remained potent in non-dividing primary cells, consistent with a post-translational mechanism. Co-treatment with the proteasome inhibitor MG132 yielded accumulation of unglycosylated PrP, demonstrating proteasome clearance of PrP. However, both compounds showed limited or no activity in human cell lines, and failed to reduce PrP in vivo after 14 days of treatment. These findings highlight the challenges associated with mechanism-agnostic phenotypic screening for PrP-lowering compounds and support prioritizing compounds with known mechanisms of action.

Indexed as

Prion ProteinsPrionsSmall Molecule LibrariesAnimalsCells, CulturedHumansMicePhenotypePrion ProteinsPrionsSmall Molecule LibrariesCell cultureCompoundsHigh-throughput screeningPrimary neuronsPrionTherapeutics

Identifiers

PMID42425332
PMCPMC13528910

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.