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Purification of the Dendritic Filopodia-rich Fraction
Published on: May 2, 2019
Presenilin/γ-secretase regulates neurexin processing at synapses
Carlos A Saura1, Emilia Servián-Morilla, Francisco G Scholl
1Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
Plos One
|May 12, 2011
Summary
Presenilins (PS) process neurexins at synapses, crucial for brain function. Impaired processing by PS may link to Alzheimer's disease (FAD) and synaptic disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Synaptic Plasticity
Background:
- Neurexins are key trans-synaptic receptors regulating synapse formation and stabilization.
- Neurexin dysfunction is linked to autism and mental retardation, but regulatory mechanisms remain unclear.
Purpose of the Study:
- To investigate the role of presenilins (PS) in neurexin processing.
- To determine if PS dysfunction impacts neurexin function at glutamatergic synapses.
- To explore the link between PS mutations and neurexin processing in familial Alzheimer's disease (FAD).
Main Methods:
- Utilized pharmacological and genetic inhibition of PS/γ-secretase in cultured neurons and mouse models.
- Analyzed neurexin C-terminal fragment (CTF) accumulation in presenilin conditional double knockout (PS cDKO) mice.
- Investigated the recruitment of presenilin 1 (PS1) to glutamatergic terminals and the effect of FAD-linked PS1 mutations on neurexin-1 processing.
Main Results:
- Inhibition of PS/γ-secretase led to significant neurexin-CTF accumulation, primarily at presynaptic terminals.
- Loss of PS function enhanced neurexin accumulation at neuroligin-1-mediated glutamatergic terminals.
- FAD-linked PS1 mutations differentially impacted β-neurexin-1 processing, with some mutants failing to rescue processing defects.
Conclusions:
- Presenilins regulate the processing and synaptic function of neurexins at glutamatergic synapses.
- Impaired neurexin processing by presenilins may contribute to the pathogenesis of familial Alzheimer's disease.
- This study reveals a novel role for PS in synaptic protein regulation with implications for neurodevelopmental and neurodegenerative disorders.
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