Cell Surface Estrogen Receptor Alpha Is Upregulated during Subchronic Metabolic Stress and Inhibits Neuronal Cell Degeneration

Abstract

In addition to the classical nuclear estrogen receptor, the expression of non-nuclear estrogen receptors localized to the cell surface membrane (mER) has recently been demonstrated. Estrogen and its receptors have been implicated in the development or progression of numerous neurodegenerative disorders. Furthermore, the pathogenesis of these diseases has been associated with disturbances of two key cellular programs: apoptosis and autophagy. An excess of apoptosis or a defect in autophagy has been implicated in neurodegeneration. The aim of this study was to clarify the role of ER in determining neuronal cell fate and the possible implication of these receptors in regulating either apoptosis or autophagy. The human neuronal cell line SH-SY5Y and mouse neuronal cells in primary culture were thus exposed to chronic minimal peroxide treatment (CMP), a form of subcytotoxic minimal chronic stress previously that mimics multiple aspects of long-term cell stress and represents a limited molecular proxy for neurodegenerative processes. We actually found that either E2 or E2-bovine serum albumin construct (E2BSA, i.e. a non-permeant form of E2) was capable of modulating intracellular cell signals and regulating cell survival and death. In particular, under CMP, the up-regulation of mERα, but not mERβ, was associated with functional signals (ERK phosphorylation and p38 dephosphorylation) compatible with autophagic cytoprotection triggering and leading to cell survival. The mERα trafficking appeared to be independent of the microfilament system cytoskeletal network but was seemingly associated with microtubular apparatus network, i.e., to MAP2 molecular chaperone. Importantly, antioxidant treatments, administration of siRNA to ERα, or the presence of antagonist of ERα hindered these events. These results support that the surface expression of mERα plays a pivotal role in determining cell fate, and that ligand-induced activation of mER signalling exerts a powerful cell-survival signal. These results shed new light on the pathogenetic mechanisms leading to neuronal cell degeneration.

Beta estradiol and norepinephrine treatment of differentiated SH-SY5Y cells enhances tau phosphorylation at (Ser396) and (Ser262) via AMPK but not mTOR signaling pathway

“…A recent study demonstrated that activation of ERα by estradiol positively regulated the p-tau (Xiong et al, 2015). Differentiated SH-SY5Y cells contains a substantial level of estradiol receptors (Barbati et al, 2012;Grassi et al, 2013). Our findings showed that exposure to NE…”

Autophagy Regulatory Network — A systems-level bioinformatics resource for studying the mechanism and regulation of autophagy

“…26,27 Also in neurodegenerative diseases, gender differences in autophagy have been described. 28 In addition, almost all neurodegenerative diseases have higher incidence in females. 22 At certain prostate cancer cell types, androgen signaling plays a cardinal role in the choice between autophagy and apoptosis, former helping survival and metastasis formation, while latter delaying tumor growth.…”

Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons

“…Membrane-initiated estradiol signaling activates the novel protein kinase PKCθ, a critical step for inducing sexual receptivity [12,13] but it is still not clear whether other signaling pathways are activated. For example, other investigators have shown that membrane-initiated signaling and the insertion of ERα into the cell membrane involve the activation of the ERK pathway [14,15,16,17]. …”