Over the years, γ-secretase has garnered intense interest from scientists and drug developers who have targeted the multimeric complex in an attempt to curb production of amyloid-β (Aβ), the peptide believed to underlie Alzheimer’s disease. Meanwhile, the list of γ-secretase substrates continues to expand, providing new research avenues as well as highlighting areas of caution from potential side effects.
In this Alzforum Webinar, Taisuke Tomita, University of Tokyo, and Rui Peixoto, Harvard Medical School, Boston, were joined for a panel discussion by Stefan Lichtenthaler, German Center for Neurodegenerative Diseases, Munich; Paul Saftig, Christian-Albrechts University, Kiel, Germany; and Carlos A. Saura, Universitat Autònoma de Barcelona, Spain. Tomita and Peixoto presented their latest data on activity-dependent processing of the postsynaptic protein neuroligin 1, a member of a larger family that has been linked to autism and that may be crucial for normal learning and memory (see ARF related news story). The panel discussed potential implications for Alzheimer’s disease and other brain disorders.
We tip our hats to Cell Press for opening access to these two papers for Alzforum readers:
Suzuki K, Hayashi Y, Nakahara S, Kumazaki H, Prox J, Horiuchi K, Zeng M, Tanimura S, Nishiyama Y, Osawa S, Sehara-Fujisawa A, Saftig P, Yokoshima S, Fukuyama T, Matsuki N, Koyama R, Tomita T, Iwatsubo T. Activity-Dependent Proteolytic Cleavage of Neuroligin 1. 18 Oct 2012;76:410-422. Free Access at Cell Press
Peixoto R, Kunz PA, Kwon H, Mabb AM, Sabatini BL, Philpot BD, Ehlers MD. Trans-Synaptic Signaling by Activity-Dependent Cleavage of Neuroligin 1. 18 Oct 2012;76:396-409. Free Access at Cell Press
- Listen to the Webinar
- Rui Peixoto's Presentation
- Taisuke Tomita's Presentation
- Carlos Saura's Presentation
by Esther Landhuis
γ-secretase has long captivated scientists studying neurodegeneration. Structure-function analyses have provided pictures of the multimeric complex, providing clues to how presenilin, its catalytic center, snakes across the membrane and interacts with amyloid-β precursor protein (APP) and other substrates (see ARF related news story). Tackling the biology of γ-secretase, scientists have opened up a whole new area of cell biology called regulated intramembrane proteolysis. Drug developers have jumped into the fray, creating compounds that inhibit or modulate γ-secretase. All so far have failed in clinical testing, the most advanced in Phase 3, where it actually worsened cognition (see ARF related news story and ARF related conference story). That made scientists wonder about potential side effects from the growing list of γ-secretase substrates, already some 40 to 50 strong.
And now comes a new one—the postsynaptic protein neuroligin 1 (NLGN1), which has been linked to autism and other brain disorders (see Südhof, 2008, review; Yanagi et al., 2012; Sun et al., 2011; Qi et al., 2009). Two papers in the October 18 Neuron report that neuronal activity promotes γ-secretase cleavage of NLGN1, stunting growth of new spines and slowing presynaptic transmitter release (see ARF related news story). As with processing of APP and Notch, the extracellular domain of NLGN1 sheds first. Here the two studies implicate different proteases. Work led by Taisuke Tomita and Takeshi Iwatsubo at the University of Tokyo points toward the APP/Notch sheddase ADAM10. The second study, conducted by Michael Ehlers and Rui Peixoto at Duke University Medical Center, Durham, North Carolina, finds that matrix metalloproteinase 9 (MMP9) sheds NLGN1 from the cell surface.
Neuroligins (NLGNs) bind to neurexins (NRXNs) in synaptic clefts. Shedding of the extracellular domains of NLGNs and subsequent processing of the C-terminal fragments by γ-secretase could have profound effects on synaptic transmission. Image reprinted by permission from Macmillan Publishers Ltd: Nature 455:903-911. Copyright 2008
What do the new data mean for AD pathogenesis and development of γ-secretase-targeting drugs? What about other neurodegenerative disorders? Neuroligins, together with their presynaptic binding partners, neurexins, are cell adhesion molecules that protrude from the cell surface and stabilize synapses (see Südhof, 2008, for a review). These interactions appear crucial for normal synaptic transmission in the developing and adult brain. Mutations in neurexin 1 and neuroligins 3 and 4 have been linked to autism, as have polymorphisms in Shank3, a scaffold protein that binds neuroligins to postsynaptic density 95. Loss of that protein frequently turns up in the context of Aβ toxicity. What happens when the neuroligin extracellular domain sheds? Are synapses destabilized? Could γ-secretase inhibitors protect synapses by blocking neuroligin processing, and how would that fit with clinical trial data?
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- Neuroligin 1—A New Substrate for γ-Secretase
- Südhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008 Oct 16;455(7215):903-11. PubMed.
- Yanagi K, Kaname T, Wakui K, Hashimoto O, Fukushima Y, Naritomi K. Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spectrum Disorder. Autism Res Treat. 2012;2012:724072. PubMed.
- Sun C, Cheng MC, Qin R, Liao DL, Chen TT, Koong FJ, Chen G, Chen CH. Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia. Hum Mol Genet. 2011 Aug 1;20(15):3042-51. PubMed.
- Qi H, Xing L, Zhang K, Gao X, Zheng Z, Huang S, Guo Y, Zhang F. Positive association of neuroligin-4 gene with nonspecific mental retardation in the Qinba Mountains Region of China. Psychiatr Genet. 2009 Feb;19(1):1-5. PubMed.