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

1. 1 121101 Alzforum webinar
Activity-dependent cleavage of Neuroligin 1
Taisuke Tomita
Graduate School of Pharmaceutical Sciences,
The University of Tokyo

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
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
Sequential cleavage of NLG1
in vitro and in vivo
NLG1 sNLG1
ADAM10
CTF ICD
Decreased shedding in ADAM10 cKO brain
-secretase

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
Inhibition of proteolytic processing of NLG1
increased the synaptogenesis
mock NLG1-FL

7. 7
Inhibition of proteolytic processing of NLG1
increased the synaptogenesis

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
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.