Huntingtin polyQ Mutation Impairs the 17β-Estradiol/Neuroglobin Pathway Devoted to Neuron Survival

Maria Teresa Nuzzo, Marco Fiocchetti, Pierangela Totta, Mariarosa A B Melone, Antonella Cardinale, Francesca R. Fusco, Stefano Gustincich, Francesca Persichetti, Paolo Ascenzi, Maria Marino

Research output: Contribution to journalArticle

Abstract

Among several mechanisms underlying the well-known trophic and protective effects of 17β-estradiol (E2) in the brain, we recently reported that E2 induces the up-regulation of two anti-apoptotic and neuroprotectant proteins: huntingtin (HTT) and neuroglobin (NGB). Here, we investigate the role of this up-regulation. The obtained results indicate that E2 promotes NGB-HTT association, induces the localization of the complex at the mitochondria, and protects SK-N-BE neuroblastoma cells and murine striatal cells, which express wild-type HTT (i.e., polyQ7), against H2O2-induced apoptosis. All E2 effects were completely abolished in HTT-knocked out SK-N-BE cells and in striatal neurons expressing the mutated form of HTT (mHTT; i.e., polyQ111) typical of Huntington’s disease (HD). As a whole, these data provide a new function of wild-type HTT which drives E2-induced NGB in mitochondria modulating NGB anti-apoptotic activity. This new function is lost by HTT polyQ pathological expansion. These data evidence the existence of a novel E2/HTT/NGB neuroprotective axis that may play a relevant role in the development of HD therapeutics.

Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalMolecular Neurobiology
DOIs
Publication statusAccepted/In press - Dec 12 2016

    Fingerprint

Keywords

  • 17β-Estradiol
  • Huntingtin
  • Huntingtin polyQ mutation
  • Neuroglobin
  • Neuron survival

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Nuzzo, M. T., Fiocchetti, M., Totta, P., Melone, M. A. B., Cardinale, A., Fusco, F. R., Gustincich, S., Persichetti, F., Ascenzi, P., & Marino, M. (Accepted/In press). Huntingtin polyQ Mutation Impairs the 17β-Estradiol/Neuroglobin Pathway Devoted to Neuron Survival. Molecular Neurobiology, 1-13. https://doi.org/10.1007/s12035-016-0337-x