PXD061828-1

PXD061828 is an original dataset announced via ProteomeXchange.

Title	Familial Alzheimer disease mutation in SORL1 impairs release of neurotrophic extracellular vesicles by microglia
Description	Coding mutations in SORL1, the gene encoding sortilin-related receptor with A-type repeats (SORLA) are common in individuals suffering from Alzheimer’s disease (AD) of unknown etiology. These findings suggest SORL1 as a novel familial disease gene causative of AD. SORL1 mutations characterized so far have mainly been shown to impact folding and maturation of the receptor polypeptide. While these previous findings support the relevance of SORLA dysfunction for AD pathology, they provide little information about activity of this intracellular sorting receptor crucial for aging brain health. Here, we have characterized the N1358S variant of SORLA, carrying a mutation in a major ligand binding domain of the receptor. Using unbiased interactome studies, we show that N1358S impacts the ability of SORLA to interact with proteins involved in formation and release of extracellular vesicle (EVs) from cells. Consequently, expression of SORLAN1358S in iPSC-derived human microglia impairs their ability to produce trophic EVs that support maturation of neurons, a defect also seen in microglia lacking the receptor. Our findings document a unique role for SORLA in microglia to neuron crosstalk through EVs, and suggest loss of neurotrophic support in the brain of SORL1N1358S carriers.
HostingRepository	PRIDE
AnnounceDate	2025-09-15
AnnouncementXML	Submission_2025-09-14_16:32:31.379.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christian Sommer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-14 04:15:54	ID requested
⏵ 1	2025-09-14 16:32:32	announced

10.1002/alz.70591;

Juul-Madsen K, Rudolph IM, Gomes JP, Meyer K, Ovesen PL, Gorniak-Walas M, Kokoli M, Telugu NS, von Tangen Sivertsen M, Febbraro F, Sutherland DS, Palmfeldt J, Diecke S, Andersen OM, Selbach M, Willnow TE, Familial Alzheimer's disease mutation identifies novel role of SORLA in release of neurotrophic exosomes. Alzheimers Dement, 21(9):e70591(2025) [pubmed]

submitter keyword: Alzheimer’s disease, extracellular vesicles,SORL1

Prof. Dr. Matthias Selbach
contact affiliation	Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Germany
contact email	matthias.selbach@mdc-berlin.de
lab head
Christian Sommer
contact affiliation	Max Delbrück Center for Molecular Medicine in the Helmholtz Association
contact email	christian.sommer@mdc-berlin.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD061828
     1. Label: PRIDE project
     2. Name: Familial Alzheimer disease mutation in SORL1 impairs release of neurotrophic extracellular vesicles by microglia