PXD038395

PXD038395 is an original dataset announced via ProteomeXchange.

Title	CRISPR-Cas9 genetic screen leads to the discovery of L-Moses, a KAT2B inhibitor that attenuates Tunicamycin-mediated neurodegeneration
Description	Accumulation of aggregated and misfolded proteins, leading to endoplasmic reticulum stress and activation of the unfolded protein response, is a hallmark of several neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Genetic screens are powerful tools that are proving invaluable in identifying novel modulators of disease associated processes. Here, we performed a loss-of-function genetic screen using a human druggable genome library, followed by an arrayed-screen validation, in human iPSC-derived cortical neurons. We identified 13 genes, whose knockout was neuroprotective against Tunicamycin, a glycoprotein synthesis inhibitor widely used to induce endoplasmic reticulum stress. We also demonstrated that pharmacological inhibition of KAT2B, a lysine acetyltransferase identified by our genetic screens, by L-Moses, attenuates Tunicamycin-mediated neuronal cell death and activation of CHOP, a key pro-apoptotic member of the unfolded protein response in both cortical and dopaminergic neurons. Follow-up transcriptional analysis suggested that L-Moses provided neuroprotection by partly reversing the transcriptional changes caused by Tunicamycin. Finally, L-Moses treatment attenuated the total protein levels affected by Tunicamycin, without affecting their acetylation profile. In summary, using an unbiased approach, we identified KAT2B and its inhibitor, L-Moses, as potential therapeutic targets for neurodegenerative diseases.
HostingRepository	PRIDE
AnnounceDate	2024-04-02
AnnouncementXML	Submission_2024-04-02_06:43:55.863.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Evangelia Papachristou
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-11-26 04:05:38	ID requested
1	2023-03-10 14:38:26	announced
2	2023-11-14 08:59:21	announced	2023-11-14: Updated project metadata.
⏵ 3	2024-04-02 06:43:56	announced	2024-04-02: Updated project metadata.

10.1038/s41598-023-31141-6;

10.1038/S41598-023-31141-6;

Pavlou S, Foskolou S, Patikas N, Field SF, Papachristou EK, Santos C, Edwards AR, Kishore K, Ansari R, Rajan SS, Fernandes HJR, Metzakopian E, CRISPR-Cas9 genetic screen leads to the discovery of L-Moses, a KAT2B inhibitor that attenuates Tunicamycin-mediated neuronal cell death. Sci Rep, 13(1):3934(2023) [pubmed]

submitter keyword: cortical neurons, KAT2B, L-Moses, endoplasmic reticulum (ER) stress,acetylome

Emmanouil Metzakopian
contact affiliation	UK Dementia Research Institute, Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, CB2 0AH, UK
contact email	em698@medschl.cam.ac.uk
lab head
Evangelia Papachristou
contact affiliation	Senior Scientific Assistant
contact email	Eva.Papachristou@cruk.cam.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD038395
     1. Label: PRIDE project
     2. Name: CRISPR-Cas9 genetic screen leads to the discovery of L-Moses, a KAT2B inhibitor that attenuates Tunicamycin-mediated neurodegeneration