Processing of the Synaptic Cell Adhesion Molecule Neurexin-3β by Alzheimer Disease α- and γ-Secretases
Open accessAbstract
Neurexins (NRXNs) are synaptic cell adhesion molecules having essential roles in the assembly and maturation of synapses into fully functional units. Immunocytochemical and electrophysiological studies have shown that specific binding across the synaptic cleft of the ectodomains of presynaptic NRXNs and postsynaptic neuroligins have the potential to bidirectionally coordinate and trigger synapse formation. Moreover, in vivo studies as well as genome-wide association studies pointed out implication of NRXNs in the pathogenesis of cognitive disorders including autism spectrum disorders and different types of addictions including opioid and alcohol dependences, suggesting an important role in synaptic function. Despite extensive investigations, the mechanisms by which NRXNs modulate the properties of synapses remain largely unknown. We report here that α- and γ-secretases can sequentially process NRXN3β, leading to the formation of two final products, an ∼80-kDa N-terminal extracellular domain of Neurexin-3β (sNRXN3β) and an ∼12-kDa C-terminal intracellular NRXN3β domain (NRXN3β-ICD), both of them being potentially implicated in the regulation of NRXNs and neuroligins functions at the synapses or in yet unidentified signal transduction pathways. We further report that this processing is altered by several PS1 mutations in the catalytic subunit of the γ-secretase that cause early-onset familial Alzheimer disease.
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NRXN3 is the isoform most consistently implicated in AD pathogenesis.
“given that this isoform has been most consistently implicated in AD pathogenesis35–39.”
From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [39]
The Results report that Alzheimer’s disease–causing PS1 mutations impair NRXN3β processing. The discussion says its possible contribution to neuronal defects still needs investigation. The paper does not establish NRXN3 as implicated in AD pathogenesis or compare how consistently different neurexin isoforms are implicated. (LLM, conf=0.86)
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- Authors
- Bot, N., Schweizer, C., Ben Halima, S., & Fraering, P. C.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Fraering, Patrick C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 286
- Issue
- 4
- Pages
- 2762-2773
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3024772
- OpenAlex
- W2075543948
- Cited by
- 81
- References
- 65
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 8 · 2021: 2 · 2020: 7 · 2019: 6 · 2018: 3 · 2017: 9 · 2016: 5 · 2015: 1 · 2014: 5 · 2013: 9 · 2012: 7
- FWCI
- 4.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- neurexin, Alzheimer's disease, alpha-secretase, gamma-secretase, presenilin 1 mutations, cytoplasmic domain, extracellular domain, synaptic cell adhesion molecules, neuroligins, synaptogenesis, familial Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Animals, Cricetulus, Cricetinae, Humans, Mutation, Nerve Tissue Proteins, Synapses, CHO Cells, Protein Structure, Tertiary, Catalytic Domain, Activated-Leukocyte Cell Adhesion Molecule, Mice, Amyloid Precursor Protein Secretases, HEK293 Cells
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