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

Abstract

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 and regeneration. Phosphoproteomic analyses demonstrate enrichment of phosphoproteins related to the epidermal growth factor (EGFR)/ERK pathway in SORLA transgenic mouse hippocampus from both genders. sSORLA coprecipitates with EGFR in vitro, and sSORLA treatment increases EGFR Y1173 phosphorylation, which is involved in ERK activation in cultured neurons. Furthermore, sSORLA triggers ERK activation, whereas pharmacological EGFR or ERK inhibition reverses sSORLA-dependent enhancement of neurite outgrowth. In search for downstream ERK effectors activated by sSORLA, we identified upregulation of Fos expression in hippocampus from male mice overexpressing SORLA by RNAseq analysis. We also found that Fos is upregulated and translocates to the nucleus in an ERK-dependent manner in neurons treated with sSORLA. Together, these results demonstrate that sSORLA is an EGFR-interacting protein that activates EGFR/ ERK/Fos signaling to enhance neurite outgrowth and regeneration.

Apamin Enhances Neurite Outgrowth and Regeneration after Laceration Injury in Cortical Neurons

“…Laceration injury has been previously described in detail [ 23 ]. Cortical neurons were cultured in a neuronal culture medium on poly-D-lysine- and laminin-coated 12 mm coverslips inside 24-well culture plates until DIV6.…”

Sorting Out Sorting Nexins Functions in the Nervous System in Health and Disease

“…Still, SNX27 pivotal role in NLGs trafficking unveils a putative role for SNX27 in pathologies that display aberrant inhibitory synaptic transmission, like mood disorders, epilepsy, and autism, among others. Recently, SORLA, a SNX27 binding partner tightly associated with AD, was also shown to modulate neurite outgrowth [197]. SORLA overexpression in cultured neurons potentiated neurite development and accelerated neurite regeneration, possibly through the activation of EGFR/ERK/Fos signaling cascade by soluble SORLA [197].…”

“…Recently, SORLA, a SNX27 binding partner tightly associated with AD, was also shown to modulate neurite outgrowth [197]. SORLA overexpression in cultured neurons potentiated neurite development and accelerated neurite regeneration, possibly through the activation of EGFR/ERK/Fos signaling cascade by soluble SORLA [197]. SNX27 binds to the cytosolic tail of SORLA promoting its translocation to the cell surface [147] and, in this manner, it can purportedly modulate the amount of soluble SORLA available and, hence, its neuroprotective role.…”

Neurotherapeutic Potential of Cervus elaphus Sibericus on Axon Regeneration and Growth Cone Reformation after H2O2-Induced Injury in Rat Primary Cortical Neurons

“…Axon regeneration was observed following CES treatment after laceration injury, with an increase in both neurite outgrowth and axon regeneration in the lacerated area. This mechanical laceration injury is the preferred in vitro model for studying neuronal injuries induced by spinal cord injury or traumatic brain injury [ 29 ]. Therefore, CES after injury in cortical neurons obviously and robustly facilitated axon regeneration.…”

“…Laceration injury was performed based on a previous method described by Stupack (2020) [ 29 ]. Briefly, cortical neurons were cultured in a neuronal culture medium on coated 12-mm glass coverslips in 24-well culture plates until day 6 in vitro.…”