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Presenilin is the molecular target of acidic ?-secretase modulators in living cells.

ABSTRACT: The intramembrane-cleaving protease ?-secretase catalyzes the last step in the generation of toxic amyloid-? (A?) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of ?-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are ?-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic A?42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP) and subunits of the ?-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers A?42 generation with an IC(50) of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN), the catalytic subunit of the ?-secretase complex, in living cells. Labeling was not observed for APP or any of the other ?-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the ?-secretase complex.

SUBMITTER: Jumpertz T

PROVIDER: S-EPMC3253113 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Presenilin is the molecular target of acidic γ-secretase modulators in living cells.

Jumpertz Thorsten T Rennhack Andreas A Ness Julia J Baches Sandra S Pietrzik Claus U CU Bulic Bruno B Weggen Sascha S

PloS one 20120106 1

The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of γ-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are γ-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amy ...[more]

PMID: 22238696

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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 ?-secretase complex that mediates the intramembraneous cleavage of several type I membrane proteins. Inhibition of PS/?-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 ?-neurexins. Furthermore, familial Alzheimer's disease (FAD)-linked PS1 mutations differentially affect ?-neurexin-1 processing. Expression of PS1 M146L and PS1 H163R mutants in PS-/- cells rescues the processing of ?-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.

Dataset Information

Presenilin is the molecular target of acidic ?-secretase modulators in living cells.

Publications

Presenilin is the molecular target of acidic γ-secretase modulators in living cells.

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