Presenilin/Ɣ-secretase regulates neurexin processing at synapses
Saura Antolín, Carlos (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Servián Morilla, Emilia (Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica)
Scholl, Francisco G. (Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica)
Fecha: |
2011 |
Resumen: |
Neurexins are a large family of neuronal plasma membrane proteins, which function as trans-synaptic receptors during synaptic differentiation. The binding of presynaptic neurexins to postsynaptic partners, such as neuroligins, has been proposed to participate in a signaling pathway that regulates synapse formation/stabilization. The identification of mutations in neurexin genes associated with autism and mental retardation suggests that dysfunction of neurexins may underlie synaptic defects associated with brain disorders. However, the mechanisms that regulate neurexin function at synapses are still unclear. Here, we show that neurexins are proteolytically processed by presenilins (PS), the catalytic components of the Ɣ-secretase complex that mediates the intramembraneous cleavage of several type I membrane proteins. Inhibition of PS/Ɣ-secretase by using pharmacological and genetic approaches induces a drastic accumulation of neurexin C-terminal fragments (CTFs) in cultured rat hippocampal neurons and mouse brain. Neurexin-CTFs accumulate mainly at the presynaptic terminals of PS conditional double knockout (PS cDKO) mice lacking both PS genes in glutamatergic neurons of the forebrain. The fact that loss of PS function enhances neurexin accumulation at glutamatergic terminals mediated by neuroligin-1 suggests that PS regulate the processing of neurexins at glutamatergic synapses. Interestingly, presenilin 1 (PS1) is recruited to glutamatergic terminals mediated by neuroligin-1, thus concentrating PS1 at terminals containing β-neurexins. Furthermore, familial Alzheimer's disease (FAD)-linked PS1 mutations differentially affect β-neurexin-1 processing. Expression of PS1 M146L and PS1 H163R mutants in PS2/2 cells rescues the processing of β-neurexin-1, whereas PS1 C410Y and PS1 ∆E9 fail to rescue the processing defect. These results suggest that PS regulate the synaptic function and processing of neurexins at glutamatergic synapses, and that impaired neurexin processing by PS may play a role in FAD. |
Ayudas: |
Instituto de Salud Carlos III CB06/05/0042
|
Nota: |
Altres ajuts: FGS/P07-CVI-02943 i CAS/SAF2010-20925 |
Derechos: |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Lengua: |
Anglès |
Documento: |
Article ; recerca ; Versió publicada |
Materia: |
Presenilines ;
Proteïnes de membranes ;
Sinapsi ;
Neurexina |
Publicado en: |
PloS one, Vol. 6 Núm. 4 (April 2011) , p. e19430, ISSN 1932-6203 |
DOI: 10.1371/journal.pone.0019430
PMID: 21559374
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