title: Huntingtin polyQ Mutation Impairs the 17β-Estradiol/Neuroglobin Pathway Devoted to Neuron Survival.
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.
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, 00146, Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Nuzzo
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, 00146, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Fiocchetti
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, 00146, Rome, Italy.
authors.forename: Pierangela
authors.initials: P
authors.lastname: Totta
authors.affiliation: Department of Medical, Surgical, Neurological, Metabolic, and Ageing Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.|Institute of Biosciences and Bioresources (IBBR-CNR), Naples, Italy.
authors.forename: Mariarosa A B
authors.initials: MAB
authors.lastname: Melone
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, 00146, Rome, Italy.|S. Lucia Foundation Hospital IRCCS, Laboratory of Neuroanatomy, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Cardinale
authors.affiliation: S. Lucia Foundation Hospital IRCCS, Laboratory of Neuroanatomy, Rome, Italy.
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Fusco
authors.affiliation: Area of Neuroscience, International School for Advanced Studies (SISSA), Trieste, Italy.|Department of Neuroscience and Brain Technologies, Italian Institute of Technologies (IIT), Genoa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gustincich
authors.affiliation: Department of Health Science, University of Eastern Piedmont, Novara, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Persichetti
authors.affiliation: Institute of Biosciences and Bioresources (IBBR-CNR), Naples, Italy.|Interdepartmental Laboratory for Electron Microscopy, Roma Tre University, Via della Vasca Navale 79, 00146, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ascenzi
authors.affiliation: Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, 00146, Rome, Italy. maria.marino@uniroma3.it.|Institute of Biosciences and Bioresources (IBBR-CNR), Naples, Italy. maria.marino@uniroma3.it.
authors.forename: Maria
authors.identifier: http://orcid.org/0000-0002-6314-3397
authors.initials: M
authors.lastname: Marino
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005914:Globins / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071058:Huntingtin Protein / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000078787:Neuroglobin; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000066829:Neuroprotection / Q000187:drug effects / Q000235:genetics; D010455:Peptides / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; D010455:Peptides; C097188:polyglutamine; D004958:Estradiol; D005914:Globins
keywords: 17β-Estradiol; Huntingtin; Huntingtin polyQ mutation; Neuroglobin; Neuron survival