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Specificity of presenilin-1- and presenilin-2-dependent ?-secretases towards substrate processing.

ABSTRACT: The two presenilin-1 (PS1) and presenilin-2 (PS2) homologs are the catalytic core of the ?-secretase complex, which has a major role in cell fate decision and Alzheimer's disease (AD) progression. Understanding the precise contribution of PS1- and PS2-dependent ?-secretases to the production of ?-amyloid peptide (A?) from amyloid precursor protein (APP) remains an important challenge to design molecules efficiently modulating A? release without affecting the processing of other ?-secretase substrates. To that end, we studied PS1- and PS2-dependent substrate processing in murine cells lacking presenilins (PSs) (PS1KO, PS2KO or PS1-PS2 double-KO noted PSdKO) or stably re-expressing human PS1 or PS2 in an endogenous PS-null (PSdKO) background. We characterized the processing of APP and Notch on both endogenous and exogenous substrates, and we investigated the effect of pharmacological inhibitors targeting the PSs activity (DAPT and L-685,458). We found that murine PS1 ?-secretase plays a predominant role in APP and Notch processing when compared to murine PS2 ?-secretase. The inhibitors blocked more efficiently murine PS2- than murine PS1-dependent processing. Human PSs, especially human PS1, expression in a PS-null background efficiently restored APP and Notch processing. Strikingly, and contrary to the results obtained on murine PSs, pharmacological inhibitors appear to preferentially target human PS1- than human PS2-dependent ?-secretase activity.

SUBMITTER: Stanga S

PROVIDER: S-EPMC5783875 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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Specificity of presenilin-1- and presenilin-2-dependent γ-secretases towards substrate processing.

Stanga Serena S Vrancx Céline C Tasiaux Bernadette B Marinangeli Claudia C Karlström Helena H Kienlen-Campard Pascal P

Journal of cellular and molecular medicine 20171010 2

The two presenilin-1 (PS1) and presenilin-2 (PS2) homologs are the catalytic core of the γ-secretase complex, which has a major role in cell fate decision and Alzheimer's disease (AD) progression. Understanding the precise contribution of PS1- and PS2-dependent γ-secretases to the production of β-amyloid peptide (Aβ) from amyloid precursor protein (APP) remains an important challenge to design molecules efficiently modulating Aβ release without affecting the processing of other γ-secretase subst ...[more]

PMID: 28994238

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Project 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.

Dataset Information

Specificity of presenilin-1- and presenilin-2-dependent ?-secretases towards substrate processing.

Publications

Specificity of presenilin-1- and presenilin-2-dependent γ-secretases towards substrate processing.

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