A NOVEL ROLE FOR POSTSYNAPTIC γ-SECRETASE IN PROMOTING WNT-MEDIATED SYNAPTIC MATURATION

Abstract

The normal developmental role of γ-secretase in neurons and at synapses is incompletely understood despite considerable study. We sought to determine if there was a role for γ-secretase components Presenilin and Nicastrin in early synapse development. Using Drosophila null mutants for psn and nct, we examined synaptic structure and organization at the larval neuromuscular junction (NMJ) using immunocytochemistry, confocal microscopy, genetics, tissue-specific rescue experiments, and protein biochemistry. We find that synaptic structure is largely normal in both psn and nct mutants, but there is a severe defect in synaptic maturation. The incidence of pre- to postsynaptic apposition failures is increased 4- to 7-fold and markers associated with a mature synapse are decreased by 85-93%. This is due to disruption in postsynaptic, not presynaptic, γ-secretase. Genetic and biochemical analyses suggest that these defects are due to faulty Wnt signaling at the NMJ – normally, the Wnt receptor Fz2 is cleaved and the C-terminus is imported into muscle nuclei to ensure maturation. This cleavage is absent in psn and nct mutants, suggesting a novel mechanism for γ-secretase by which it cleaves Fz2 to promote synaptic maturation and early development. γ-secretase has a novel role in synaptic maturation, via developmental cleavage of a postsynaptic Wnt receptor. This raises the possibility that early events in synaptic maturation can be linked to later-onset neurodegenerative diseases.