Presenilin/γ-secretase regulates neurexin processing at synapses.

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 sy...

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Autores principales:	Carlos A Saura, Emilia Servián-Morilla, Francisco G Scholl
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ceb55d1f53d34f9496383617cd425375
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spelling	oai:doaj.org-article:ceb55d1f53d34f9496383617cd4253752021-11-18T06:54:52ZPresenilin/γ-secretase regulates neurexin processing at synapses.1932-620310.1371/journal.pone.0019430https://doaj.org/article/ceb55d1f53d34f9496383617cd4253752011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21559374/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Neurexins 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 γ-secretase complex that mediates the intramembraneous cleavage of several type I membrane proteins. Inhibition of PS/γ-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 PS-/- cells rescues the processing of β-neurexin-1, whereas PS1 C410Y and PS1 ΔE9 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.Carlos A SauraEmilia Servián-MorillaFrancisco G SchollPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 4, p e19430 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Carlos A Saura Emilia Servián-Morilla Francisco G Scholl Presenilin/γ-secretase regulates neurexin processing at synapses.
description	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 γ-secretase complex that mediates the intramembraneous cleavage of several type I membrane proteins. Inhibition of PS/γ-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 PS-/- cells rescues the processing of β-neurexin-1, whereas PS1 C410Y and PS1 ΔE9 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.
format	article
author	Carlos A Saura Emilia Servián-Morilla Francisco G Scholl
author_facet	Carlos A Saura Emilia Servián-Morilla Francisco G Scholl
author_sort	Carlos A Saura
title	Presenilin/γ-secretase regulates neurexin processing at synapses.
title_short	Presenilin/γ-secretase regulates neurexin processing at synapses.
title_full	Presenilin/γ-secretase regulates neurexin processing at synapses.
title_fullStr	Presenilin/γ-secretase regulates neurexin processing at synapses.
title_full_unstemmed	Presenilin/γ-secretase regulates neurexin processing at synapses.
title_sort	presenilin/γ-secretase regulates neurexin processing at synapses.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/ceb55d1f53d34f9496383617cd425375
work_keys_str_mv	AT carlosasaura presenilingsecretaseregulatesneurexinprocessingatsynapses AT emiliaservianmorilla presenilingsecretaseregulatesneurexinprocessingatsynapses AT franciscogscholl presenilingsecretaseregulatesneurexinprocessingatsynapses
_version_	1718424257064599552

Presenilin/γ-secretase regulates neurexin processing at synapses.

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