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.
Highlights
Several lines of evidence indicate that 17b-estradiol (E2) directly modulates the development and function of neurons, the mechanism(s) by which this might occur is not well understood [1,2,3]
Since chronic minimal peroxide (CMP) induced reactive oxygen species (ROS) generation and a mild oxidative imbalance in the cell cytoplasm [22], we decided to evaluate the possible implication of ROS generation in the upmodulation of mERa by pre-treating SH-SY5Y cells with Nacetyl-L-cysteine (NAC)
Since SH-SY5Y cells have to be considered as highly proliferating cells of tumor origin, we further evaluated the expression of mERa in differentiated neurons
Summary
Several lines of evidence indicate that 17b-estradiol (E2) directly modulates the development and function of neurons, the mechanism(s) by which this might occur is not well understood [1,2,3]. A variety of cellular responses to physiological concentrations of E2 occurs rapidly, within seconds to few minutes, so that they cannot be mediated by transcription and protein synthesis These rapid estrogen-mediated effects (referred to as ‘‘nongenomic’’) are triggered through the activation of non-nuclear membraneassociated ER (mER) [4,5,6,7,8]. It has been suggested that the E2-dependent nongenomic signaling, by hindering apoptotic cell death, mediates neuroprotection and preservation of cognitive function following global cerebral ischemia, supporting a potentially important role of nonnuclear mER [12] In this regard, the expression levels of mERa and mERb, acting independently from nuclear ER, have been demonstrated to trigger a functional and prompt cell response. This appears to play a key role in mediating estrogen’s effects: an increased expression of mERa has to be considered as protective
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