Evidence map›Paper›PMID 40015642›Full record

ArticleThe Journal of biological chemistry2025

A high-throughput assay platform to discover small molecule activators of the phospholipase PLC-γ2 to treat Alzheimer's disease.

Adam J Carr, Nicole Hajicek, Andy P Tsai, Padam P Acharya, P Brian Hardy, Emma Meyer, Tony Wyss-Coray, Kenneth H Pearce, John Sondek, Qisheng Zhang

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of biological chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing 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

4 citing papers in PubMed.

  1. LAT condensation gates PLCγ1 activation via bimodal LAT phosphorylation.Proceedings of the National Academy of Sciences of the United States of America · 2026
    Article
  2. Review
  3. Article
  4. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Adam J CarrDivision of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Nicole HajicekDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Andy P TsaiWu Tsai Neurosciences Institute, Stanford University, Stanford, California, USA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
Padam P AcharyaDivision of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
P Brian HardyCenter for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Emma MeyerDivision of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Tony Wyss-CorayWu Tsai Neurosciences Institute, Stanford University, Stanford, California, USA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
Kenneth H PearceDivision of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Center for Integrative Chemical Biology and Drug Discovery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
John SondekDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Qisheng ZhangDivision of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Electronic address: qszhang@unc.edu.

Funding

Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Deborah F. Tate · 1985 to 2026
$201.5M
A high-throughput platform to identify selective allosteric inhibitors of the PLC-y isozymesR01CA258993 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI PEARCE, KENNETH HUGH, SONDEK, JOHN E · 2021 to 2024
$2.2M
Phospholipase C IsozymesR35GM149299 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI JOHN E SONDEK · 2023 to 2026
$1.7M
Discovery of allosteric activators of phospholipase C-gamma2 to treat Alzheimer's diseaseR56AG083424 · NIA · UNIV OF NORTH CAROLINA CHAPEL HILL · PI PEARCE, KENNETH HUGH, SONDEK, JOHN E · 2023 to 2024
$1.5M
NCI NIH HHS P30 CA016086NCI NIH HHS R01 CA258993NIA NIH HHS R56 AG083424NIGMS NIH HHS R35 GM149299
6 · The paper itself

Abstract

A naturally occurring missense variant of the phospholipase C isozyme, PLC-γ2, harboring a single substitution (P522R) protects against several neurodegenerative diseases, including Alzheimer's disease. The phospholipase activity of PLC-γ2 (P522R) is slightly elevated relative to its WT counterpart, and the general consensus is that this increased activity in microglia confers protection against neurodegeneration. In order to phenocopy this protection, we have developed a high-throughput assay to identify small molecule activators of PLC-γ2. The assay takes advantage of the fluorescent reporter, XY-69, embedded in lipid vesicles to readout the allosteric activation of PLC-γ2. The assay is highly reproducible and capable of identifying compounds with a large range of efficacies. A series of secondary assays have been established to define the selectivity of compounds for PLC-γ2, establish relevant activation of PLC-γ2 by compounds in a microglia cell line, and measure affinities between PLC-γ2 and hit compounds. The established workflow was prototyped using approximately 6000 compounds to produce several promising hits, but more importantly, enables screens of much larger chemical libraries to identify selective activators of PLC-γ2 to be used as chemical probes and drug leads.

Indexed as

Alzheimer DiseaseEnzyme ActivatorsHigh-Throughput Screening AssaysPhospholipase C gammaSmall Molecule LibrariesAnimalsCell LineEnzyme ActivationHumansMicrogliaEnzyme ActivatorsPhospholipase C gammaSmall Molecule Librariesallosteric regulationAlzheimer's diseasehigh-throughput screeninglipid metabolismmicrogliaphagocytosisphospholipase Csmall molecule activators

Identifiers

PMID40015642
PMCPMC12131191

What OpenQuestion holds

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Registered trials

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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.