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

8 Citations (Scopus)

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

Estradiol
Neurons
Mutation
Corpus Striatum
Huntington Disease
Mitochondria
Up-Regulation
Apoptosis Regulatory Proteins
Neuroprotective Agents
Neuroblastoma
neuroglobin
polyglutamine
Apoptosis
Brain
Therapeutics

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., ... 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

Huntingtin polyQ Mutation Impairs the 17β-Estradiol/Neuroglobin Pathway Devoted to Neuron Survival. / Nuzzo, Maria Teresa; Fiocchetti, Marco; Totta, Pierangela; Melone, Mariarosa A B; Cardinale, Antonella; Fusco, Francesca R.; Gustincich, Stefano; Persichetti, Francesca; Ascenzi, Paolo; Marino, Maria.

In: Molecular Neurobiology, 12.12.2016, p. 1-13.

Research output: Contribution to journalArticle

Nuzzo, MT, Fiocchetti, M, Totta, P, Melone, MAB, Cardinale, A, Fusco, FR, Gustincich, S, Persichetti, F, Ascenzi, P & Marino, M 2016, 'Huntingtin polyQ Mutation Impairs the 17β-Estradiol/Neuroglobin Pathway Devoted to Neuron Survival', Molecular Neurobiology, pp. 1-13. https://doi.org/10.1007/s12035-016-0337-x
Nuzzo, Maria Teresa ; Fiocchetti, Marco ; Totta, Pierangela ; Melone, Mariarosa A B ; Cardinale, Antonella ; Fusco, Francesca R. ; Gustincich, Stefano ; Persichetti, Francesca ; Ascenzi, Paolo ; Marino, Maria. / Huntingtin polyQ Mutation Impairs the 17β-Estradiol/Neuroglobin Pathway Devoted to Neuron Survival. In: Molecular Neurobiology. 2016 ; pp. 1-13.
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