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ADAM10 hyperactivation acts on piccolo to deplete synaptic vesicle stores in Huntington's disease
- Source :
- Human molecular genetics. 30(13)
- Publication Year :
- 2020
-
Abstract
- Synaptic dysfunction and cognitive decline in Huntington’s disease (HD) involve hyperactive A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10). To identify the molecular mechanisms through which ADAM10 is associated with synaptic dysfunction in HD, we performed an immunoaffinity purification–mass spectrometry (IP–MS) study of endogenous ADAM10 in the brains of wild-type and HD mice. We found that proteins implicated in synapse organization, synaptic plasticity, and vesicle and organelles trafficking interact with ADAM10, suggesting that it may act as hub protein at the excitatory synapse. Importantly, the ADAM10 interactome is enriched in presynaptic proteins and ADAM10 co-immunoprecipitates with piccolo (PCLO), a key player in the recycling and maintenance of synaptic vesicles. In contrast, reduced ADAM10/PCLO immunoprecipitation occurs in the HD brain, with decreased density of synaptic vesicles in the reserve and docked pools at the HD presynaptic terminal. Conditional heterozygous deletion of ADAM10 in the forebrain of HD mice reduces active ADAM10 to wild-type level and normalizes ADAM10/PCLO complex formation and synaptic vesicle density and distribution. The results indicate that presynaptic ADAM10 and PCLO are a relevant component of HD pathogenesis.
- Subjects :
- Proteomics
ADAM10
Blotting, Western
Presynaptic Terminals
Biology
Synaptic vesicle
03 medical and health sciences
ADAM10 Protein
0302 clinical medicine
Excitatory synapse
Huntington's disease
Microscopy, Electron, Transmission
Tandem Mass Spectrometry
Genetics
medicine
Animals
Humans
Protein Interaction Maps
Cognitive decline
Molecular Biology
Synapse organization
Genetics (clinical)
030304 developmental biology
Mice, Knockout
0303 health sciences
presynaptic terminalsimmunoprecipitationhuntington's diseasedisintegrinsheterozygotemetalloproteasesneuronal plasticityorganellesprosencephalonsynapsessynaptic vesiclesbrainmicecognitive impairmentvesicleelav-like protein 2
Neuropeptides
Brain
General Medicine
medicine.disease
Cell biology
Mice, Inbred C57BL
Cytoskeletal Proteins
Huntington Disease
Synaptic plasticity
Forebrain
Synaptic Vesicles
030217 neurology & neurosurgery
Protein Binding
Synaptosomes
Subjects
Details
- ISSN :
- 14602083
- Volume :
- 30
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- Human molecular genetics
- Accession number :
- edsair.doi.dedup.....652018dcef7810a442dd374efa62318d