Soluble SORLA enhances neurite outgrowth and regeneration through activation of EGFR and MAPK pathways

ABSTRACT: SORLA is a type I transmembrane component associated with Alzheimers disease (AD) risk. Although SORLA is abundantly expressed in neurons, physiological roles for SORLA remain yet unclear. Here, we show that cultured neurons overexpressing SORLA (SORLA TG) feature enhanced neurite length, and accelerated neurite regeneration with wounding. Enhanced accumulation of a soluble SORLA form (sSORLA) is observed in SORLA TG neurons, where purified sSORLA can sufficiently drive neurite extension and regeneration. Phosphoproteomic analysis indicates enrichment of phosphoproteins related to the EGFR/ERK pathway in SORLA TG hippocampus. We find that sSORLA can co-precipitate with EGFR in vitro, where sSORLA treatment can induce EGFR Y1173 phosphorylation in cultured neurons. sSORLA also triggers Erk activation and downstream c-fos upregulation/nuclear translocation, where pharmacological EGFR or ERK inhibition reversed enhancements in sSORLA-dependent neurite regeneration. Together, these results implicate the EGFR as a sSORLA receptor which activates ERK/c-Fos pathways to enhance neurite extension, outgrowth and regeneration.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Timothy Y. Huang  

PROVIDER: MSV000085400 | MassIVE | Tue May 12 00:39:00 BST 2020

SECONDARY ACCESSION(S): PXD019109

REPOSITORIES: MassIVE