Taisuke tomita

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Presentation made by Dr. Taisuke Tomita, November 1, 2012 on Alzheimer Research Forum (www.alzforum.org)

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Taisuke tomita

  1. 1. 1 121101 Alzforum webinar Activity-dependent cleavage of Neuroligin 1 Taisuke Tomita Graduate School of Pharmaceutical Sciences, The University of Tokyo
  2. 2. 2 Neuroligin/Neurexin system  Neuroligin 1 (NLG1) is a postsynaptic molecule involved in synaptogenesis.  Aberrant expression of NLG1 has been implicated in the pathogenesis of Autism spectrum disorder.  Little information had been available regarding the regulation of protein levels of NLG1.
  3. 3. 3 Sequential cleavage of NLG1 in vitro and in vivo Rat brain Primary neuron DAPT TAPI2 NLG1 sNLG1 Medium sNLG1 ADAM10 NLG1-FL Lysate NLG1-CTF III-tubulin CTF ICD -secretase
  4. 4. 4 Sequential cleavage of NLG1 in vitro and in vivo NLG1 sNLG1 ADAM10 CTF ICD Decreased shedding in ADAM10 cKO brain -secretase
  5. 5. 5 Activity dependent processing of NLG1 in vitro and in vivo pilocarpine a.u. Status Epilepsy (SE) Soluble fraction sNLG1 NLG1 Membrane cerebrum fraction
  6. 6. 6 Inhibition of proteolytic processing of NLG1 increased the synaptogenesis mock NLG1-FL
  7. 7. 7 Inhibition of proteolytic processing of NLG1 increased the synaptogenesis
  8. 8. 8 Inhibitory modulation of synaptogenic activity of Neuroligin by proteolysis sNRX Synaptic loss? NX Neuroligin Synaptic ADAM10 CTF -secretase activity Activate! NMDA receptor FL CTF PSD-95 PSD-95 PSD-95 ICD
  9. 9. 9 Summary  Neuroligin 1 is sequentially cleaved by ADAM10 and - secretase.  Shedding of neuroligin 1 is modulated by neuronal activity and ligand binding.  Neuroligin 1 cleavage is upregulated by epileptic seizure condition in vivo.  Proteolytic processing of neuroligin 1 negatively regulates spine formation.

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