PXD036727-3

PXD036727 is an original dataset announced via ProteomeXchange.

Title	Altered plasma membrane abundance of the sulfatide-binding protein NF155 links glycosphingolipid imbalances to demyelination
Description	Myelination of axons enables efficient signal propagation in neurones. Myelin is a multi-layered membrane that wraps around neuronal axons forming extremely tight contacts that insulate the axon. Tight contact between the axon and myelin sheath is mediated by specific plasma membrane proteins and lipids, with disruption to these contacts causing devastating demyelinating diseases. We have generated two cell-based models of demyelinating sphingolipidoses and shown that the altered lipid metabolism changes the plasma membrane protein composition. The proteins that are altered in these cells play roles in cell adhesion and signalling, several of which have previously been implicated in a range of neurological diseases. The adhesion molecule Neurofascin, with a known role in myelin-axon contact sites, is significantly altered in response to sphingolipid imbalances, highlighting a potential new player contributing to the pathogenesis of galactosphingolipid-mediated diseases. We show that the Neurofascin isoform NF155, but not NF186, directly binds the sphingolipid sulfatide, but does not bind other galactosylated-sphingolipids. Furthermore, this interaction requires the full-length extracellular domain of NF155 and that the structure of this domain adopts an S-shape with important implications for the arrangement of proteins in the tight axon-myelin space. Together, this work identifies that glycosphingolipid imbalances drive changes in membrane protein abundance and that this may be driven by direct interactions between extracellular portions of these proteins with specific lipid headgroups.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:44:40.959.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD036727
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	James Williamson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-09-14 03:20:37	ID requested
1	2023-04-06 02:55:01	announced
2	2023-11-14 08:57:44	announced	2023-11-14: Updated project metadata.
⏵ 3	2024-10-22 05:44:41	announced	2024-10-22: Updated project metadata.

10.6019/PXD036727;

10.1073/PNAS.2218823120;

submitter keyword: galactosylceramide, neurofascin, myelination, sulfatide,Krabbe Disease

Paul Lehner
contact affiliation	Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge,
contact email	pjl30@cam.ac.uk
lab head
James Williamson
contact affiliation	University of Cambridge
contact email	jcw76@cam.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD036727
     1. Label: PRIDE project
     2. Name: Altered plasma membrane abundance of the sulfatide-binding protein NF155 links glycosphingolipid imbalances to demyelination