Estrogen Modulates ubc9 Expression and Synaptic Redistribution in the Brain of APP/PS1 Mice and Cortical Neurons
Estrogen exerts multiple actions in the brain and is an important neuroprotective factor in a number of neuronal disorders. However, the underlying mechanism remains unknown. Studies demonstrate that ubiquitin-conjugating enzyme 9 (ubc9) has an integral role in synaptic plasticity and may contribute to the pathology of neuronal disorders. We aimed to investigate the effects of estrogen on ubc9 and in the Alzheimer’s disease brain. Ubc9 protein and mRNA were significantly increased in the cortex and hippocampus of APP/PS1 mice with enhanced SUMOylation. Systemic estrogen administration led to reduced ubc9 expression in ovariectomized APP/PS1 mice and reduced SUMOylation. The inhibition of ubc9 expression by estrogen was found to be dose-dependent in cultured neurons. However, estrogen receptor (ER) antagonist ICI182780 did not block the inhibition of ubc9 expression by estrogen. Furthermore, the reduced expression of ubc9 was not mediated by ERα or ERβ agonists alone or in combination, but by the membrane-impermeable ER agonist E2-bovine serum albumin. The activation of the G protein-coupled ER mediated the inhibition of ubc9 expression of estrogen. A phosphoinositide 3-kinase (PI3K) inhibitor, rather than an extracellular signal-regulated kinase inhibitor, blocked the inhibition of ubc9 by estrogen. Estrogen treatment significantly increased the phosphorylation of PI3K, which suggests that activation of the PI3K pathway by estrogen is required for ubc9 regulation. Further, ubc9 interacted with the synaptic proteins post-synaptic density protein 95 (PSD95) and synaptophysin. Estrogen decreased the interaction of ubc9 with post-synaptic PSD95, but increased the interaction of ubc9 with pre-synaptic synaptophysin. These results suggest that a membrane-bound ER might mediate the estrogen inhibition of ubc9 in cortical neurons, where PI3K plays an important role. We also show that ubc9 can interact with synaptic proteins, which are subject to estrogen regulation.
KeywordsEstrogen ubc9 Neuroplasticity PSD95 Synaptophysin
This work was supported by NSFC grants (numbers 81171197 and 81220108010) and a Bureau of Health of Chongqing Medical Research grant (number 2011-1-018) to G-J. C.
Compliance with Ethical Standards
All protocols were approved by the Commission of Chongqing Medical University for Ethics of Experiments on Animals and were conducted in accordance with international standards.
The authors declare that they have no competing interests.
- Chu Z, Andrade J, Shupnik MA, Moenter SM (2009) Differential regulation of gonadotropin-releasing hormone neuron activity and membrane properties by acutely applied estradiol: dependence on dose and estrogen receptor subtype. J Neurosci : Off JSoc Neurosci 29:5616–5627. doi: 10.1523/jneurosci.0352-09.2009 CrossRefGoogle Scholar
- Grove-Strawser D, Boulware MI, Mermelstein PG (2010) Membrane estrogen receptors activate the metabotropic glutamate receptors mGluR5 and mGluR3 to bidirectionally regulate CREB phosphorylation in female rat striatal neurons. Neuroscience 170:1045–1055. doi: 10.1016/j.neuroscience.2010.08.012 CrossRefPubMedPubMedCentralGoogle Scholar
- Loriol C, Khayachi A, Poupon G, Gwizdek C, Martin S (2013) Activity-dependent regulation of the sumoylation machinery in rat hippocampal neurons biology of the cell / under the auspices of the European Cell Biology Organization 105:30–45 doi: 10.1111/boc.201200016
- Mannella P, Brinton RD (2006) Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. J Neurosci: Off J Soc Neurosci 26:9439–9447. doi: 10.1523/jneurosci.1443-06.2006 CrossRefGoogle Scholar
- Okun E, Arumugam TV, Tang SC, Gleichmann M, Albeck M, Sredni B, Mattson MP (2007) The organotellurium compound ammonium trichloro(dioxoethylene-0,0′) tellurate enhances neuronal survival and improves functional outcome in an ischemic stroke model in mice. J Neurochem 102:1232–1241. doi: 10.1111/j.1471-4159.2007.04615.x CrossRefPubMedGoogle Scholar
- Paul SM, Purdy RH (1992) Neuroactive steroids. FASEB J: Off Publ Fed Am Soc Exp Biol 6:2311–2322Google Scholar
- Qiu J, Bosch MA, Tobias SC, Grandy DK, Scanlan TS, Ronnekleiv OK, Kelly MJ (2003) Rapid signaling of estrogen in hypothalamic neurons involves a novel G-protein-coupled estrogen receptor that activates protein kinase C. J Neurosci: J Soc Neurosci 23:9529–9540Google Scholar
- Toran-Allerand CD et al (2002) ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J Neurosci: Off J Soc Neurosci 22:8391–8401Google Scholar
- Woolley CS, Gould E, Frankfurt M, McEwen BS (1990) Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci: Off J Soc Neurosci 10:4035–4039Google Scholar