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Phenylpiperidine-type ?-secretase modulators target the transmembrane domain 1 of presenilin 1.

ABSTRACT: Amyloid-? peptide ending at the 42nd residue (A?42) is implicated in the pathogenesis of Alzheimer's disease (AD). Small compounds that exhibit selective lowering effects on A?42 production are termed ?-secretase modulators (GSMs) and are deemed as promising therapeutic agents against AD, although the molecular target as well as the mechanism of action remains controversial. Here, we show that a phenylpiperidine-type compound GSM-1 directly targets the transmembrane domain (TMD) 1 of presenilin 1 (PS1) by photoaffinity labelling experiments combined with limited digestion. Binding of GSM-1 affected the structure of the initial substrate binding and the catalytic sites of the ?-secretase, thereby decreasing production of A?42, possibly by enhancing its conversion to A?38. These data indicate an allosteric action of GSM-1 by directly binding to the TMD1 of PS1, pinpointing the target structure of the phenylpiperidine-type GSMs.

SUBMITTER: Ohki Y

PROVIDER: S-EPMC3243616 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1.

Ohki Yu Y Higo Takuya T Uemura Kengo K Shimada Naoaki N Osawa Satoko S Berezovska Oksana O Yokoshima Satoshi S Fukuyama Tohru T Tomita Taisuke T Iwatsubo Takeshi T

The EMBO journal 20111014 23

Amyloid-β peptide ending at the 42nd residue (Aβ42) is implicated in the pathogenesis of Alzheimer's disease (AD). Small compounds that exhibit selective lowering effects on Aβ42 production are termed γ-secretase modulators (GSMs) and are deemed as promising therapeutic agents against AD, although the molecular target as well as the mechanism of action remains controversial. Here, we show that a phenylpiperidine-type compound GSM-1 directly targets the transmembrane domain (TMD) 1 of presenilin ...[more]

PMID: 22002539

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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.

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Phenylpiperidine-type ?-secretase modulators target the transmembrane domain 1 of presenilin 1.

Publications

Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1.

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