PXD048283

PXD048283 is an original dataset announced via ProteomeXchange.

Title	Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons
Description	Alpha-synuclein (αSyn) protein levels correlate with the risk and severity of Parkinson's disease and related neurodegenerative diseases. Lowering αSyn is being actively investigated as a therapeutic modality. Here we systematically map the regulatory network that controls endogenous αSyn using sequential CRISPR-knockout and -interference screens in αSyn gene(SNCA) tagged cell lines and induced pluripotent stem cell-derived neurons (iNeurons). We uncover αSyn modifiers at multiple regulatory layers, with N-terminal acetyltransferase B (NatB) enzymes being the most potent endogenous αSyn modifier in both cell lines. N-terminal acetylation protects the cytosolic αSyn from rapid degradation by the proteasome in a Ube2Wdependent manner. Moreover, we show that pharmacological inhibition of methionylaminopeptidase 2 (METAP2), a regulator of NatB complex formation, attenuates endogenous αSyn in iNeurons carrying SNCA triplication. Together, our study reveals several gene networks that control endogenous αSyn, identifies mechanisms mediating the degradation of nonacetylated αSyn and illustrates potential therapeutic pathways for decreasing αSyn levels in synucleinopathies.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:41:02.918.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hossein Fazelinia
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-01-05 11:21:43	ID requested
1	2024-05-22 02:01:01	announced
⏵ 2	2024-10-22 06:41:11	announced	2024-10-22: Updated project metadata.

10.1126/sciadv.adj4767;

Santhosh Kumar S, Naseri NN, Pather SR, Hallacli E, Ndayisaba A, Buenaventura C, Acosta K, Roof J, Fazelinia H, Spruce LA, Luk K, Khurana V, Rhoades E, Shalem O, Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons. Sci Adv, 10(6):eadj4767(2024) [pubmed]

submitter keyword: CRISPR, Alpha-synuclein, NatB inhibition, Parkinson's disease, human neurons

Ophir Shalem, Ph.D.
contact affiliation	Assistant Professor of Genetics Genetics Department University of Pennsylvania 5050 Colket Translational Research Building 3501 Civic Center Boulevard Philadelphia, PA 19104
contact email	shalemo@upenn.edu
lab head
Hossein Fazelinia
contact affiliation	Children's Hospital of Philadelphia
contact email	fazeliniah@email.chop.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/05/PXD048283

PRIDE project URI

• PRIDE
  1. PXD048283
     1. Label: PRIDE project
     2. Name: Sequential CRISPR screening reveals partial NatB inhibition as a strategy to mitigate alpha-synuclein levels in human neurons