Adhesion protein NEGR1 shapes mGlu5 signalling and PAM neuroprotection
- Mass spectrometry and co-immunoprecipitation identified NEGR1 as a binding partner of mGlu5, whose positive allosteric modulators (PAMs) are biased agonists promoting neuronal survival.
- In primary neurons lacking NEGR1, the interaction was needed for mGlu5 synaptic localization and Homer coupling.
- NEGR1 loss weakened ERK1/2 activation and lowered ARC/Arg3.1 and BDNF; its role in neuroprotection by the PAM VU0409551 was tested via apoptosis and neurite degeneration.
💡 Points
Does the PAM's neuroprotection actually need NEGR1? That's the experiment to run first, because a scaffold-dependent mechanism means efficacy could vary with NEGR1 levels across neurons, brain regions and people. Knockdown in cultured primary neurons is also a long way from an intact brain; a rescue experiment and in vivo evidence would have to come before I leaned on it.