Dataset Information

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

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Publications

Soluble SORLA Enhances Neurite Outgrowth and Regeneration through Activation of the EGF Receptor/ERK Signaling Axis.

Stupack Jessica J Xiong Xiao-Peng XP Jiang Lu-Lin LL Zhang Tongmei T Zhou Lisa L Campos Alex A Ranscht Barbara B Mobley William W Pasquale Elena B EB Xu Huaxi H Huang Timothy Y TY

The Journal of neuroscience : the official journal of the Society for Neuroscience 20200629 31

SORLA is a transmembrane trafficking protein associated with Alzheimer's disease risk. Although SORLA is abundantly expressed in neurons, physiological roles for SORLA remain unclear. Here, we show that cultured transgenic neurons overexpressing SORLA feature longer neurites, and accelerated neurite regeneration with wounding. Enhanced release of a soluble form of SORLA (sSORLA) is observed in transgenic mouse neurons overexpressing human SORLA, while purified sSORLA promotes neurite extension a ...[more]

PMID: 32601248

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