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Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity

Gaël Barthet, Tomàs Jordà-Siquier, Julie Rumi-Masante, Fanny Bernadou, Ulrike Müller, Christophe Mulle
doi: https://doi.org/10.1101/258335
Gaël Barthet
1Interdisciplinary Institute for Neuroscience, CNRS UMR 5297
2University of Bordeaux, F-33000 Bordeaux, France
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Tomàs Jordà-Siquier
1Interdisciplinary Institute for Neuroscience, CNRS UMR 5297
2University of Bordeaux, F-33000 Bordeaux, France
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Julie Rumi-Masante
1Interdisciplinary Institute for Neuroscience, CNRS UMR 5297
2University of Bordeaux, F-33000 Bordeaux, France
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Fanny Bernadou
1Interdisciplinary Institute for Neuroscience, CNRS UMR 5297
2University of Bordeaux, F-33000 Bordeaux, France
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Ulrike Müller
3Institute for Pharmacy and Molecular Biotechnology, Im Neuenheimer Feld 364, Heidelberg, Germany
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Christophe Mulle
1Interdisciplinary Institute for Neuroscience, CNRS UMR 5297
2University of Bordeaux, F-33000 Bordeaux, France
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  • For correspondence: christophe.mulle@u-bordeaux.fr gael.barthet@u-bordeaux.fr
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SUMMARY

Presenilin (PS), the catalytic subunit of γ-secretase and its main substrate the amyloid precursor protein (APP) are mutated in a large majority of patients with familial Alzheimer disease. PS and APP interact with proteins of the neurotransmitter release machinery but the functional consequences of these interactions are unknown. Here we report that genetic deletion of presynaptic PS markedly decreases the axonal expression of the Ca2+ sensor synaptotagmin-7 (Syt7), and impairs synaptic facilitation and replenishment of release-competent synaptic vesicles. These properties are fully restored by presynaptic re-expression of Syt7. The regulation of Syt7 expression occurs post-transcriptionally and depends on γ-secretase activity. In the combined absence of both APP and PS1, the loss of Syt7 is prevented, indicating that the action of γ-secretase on presynaptic mechanisms depends on its substrate APP. The molecular mechanism involves the substrate of PS, APP-βCterminal (APP-βCTF), which interacts with Syt7 and accumulates in synaptic terminals under conditions of pharmacological or genetic inhibition of γ-secretase. These results reveal a role of PS in presynaptic mechanisms through regulation of Syt7 by APP-dependent cleavage, and highlight aberrant synaptic vesicle processing as a possible new pathway in AD.

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Posted February 01, 2018.
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Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity
Gaël Barthet, Tomàs Jordà-Siquier, Julie Rumi-Masante, Fanny Bernadou, Ulrike Müller, Christophe Mulle
bioRxiv 258335; doi: https://doi.org/10.1101/258335
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Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity
Gaël Barthet, Tomàs Jordà-Siquier, Julie Rumi-Masante, Fanny Bernadou, Ulrike Müller, Christophe Mulle
bioRxiv 258335; doi: https://doi.org/10.1101/258335

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