PXD052118-1

PXD052118 is an original dataset announced via ProteomeXchange.

Title	Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system
Description	INPP5D, which encodes the lipid phosphatase SHIP1, is one of the most common genes associated with the risk of Alzheimer’s disease and is enriched in microglia in the central nervous system. SHIP1 has been found to be highly expressed in plaque-associated microglia. However, how it regulates microglial function and influences brain physiology has been poorly investigated. Here we show that SHIP1 is not only enriched in microglia associated with amyloid beta plaques, but also in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that conditional knockout mice lacking microglial SHIP1 (cKO) display increased complement and synapse loss in the early postnatal brain. Additionally, SHIP1 KO microglia show reduced morphological complexity, altered transcriptional signatures, and abnormal synaptic pruning, which is dependent on the complement system. Single nucleus RNA-sequencing analysis of the entire hippocampus confirmed decreased interaction for synaptic structure-related pathways in both excitatory and inhibitory neurons. Importantly, cKO mice show cognitive defects in adulthood only when microglial SHIP1 is depleted at early postnatal days, but not when depleted at later stages. Finally, using CRISPR/Cas9 we generated human iPSC-derived microglia lacking SHIP1, and validated the increased engulfment of synaptic structures. Altogether, these findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling through the complement system in the early postnatal brain. Disrupting this process has lasting behavioral effects and may provide a link to vulnerability to neurodegeneration.
HostingRepository	PRIDE
AnnounceDate	2024-12-04
AnnouncementXML	Submission_2024-12-04_00:00:03.903.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Rosa Chiara Paolicelli
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-08 10:19:04	ID requested
⏵ 1	2024-12-04 00:00:04	announced

Dataset with its publication pending

submitter keyword: complement, SHIP1, synaptic pruning, INPP5D,Microglia

Rosa C. Paolicelli
contact affiliation	UNIL – Department of Biomedical Sciences. Rue du Bugnon 7, 1005, Lausanne.
contact email	rosachiara.paolicelli@unil.ch
lab head
Rosa Chiara Paolicelli
contact affiliation	University of Lausanne, Department of Biomedical Sciences, Lausanne
contact email	rosachiara.paolicelli@unil.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD052118
     1. Label: PRIDE project
     2. Name: Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system