TY - JOUR
T1 - Huntingtin polyQ Mutation Impairs the 17β-Estradiol/Neuroglobin Pathway Devoted to Neuron Survival
AU - Nuzzo, Maria Teresa
AU - Fiocchetti, Marco
AU - Totta, Pierangela
AU - Melone, Mariarosa A.B.
AU - Cardinale, Antonella
AU - Fusco, Francesca R.
AU - Gustincich, Stefano
AU - Persichetti, Francesca
AU - Ascenzi, Paolo
AU - Marino, Maria
N1 - Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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.
KW - 17β-Estradiol
KW - Huntingtin
KW - Huntingtin polyQ mutation
KW - Neuroglobin
KW - Neuron survival
UR - https://www.scopus.com/pages/publications/85003837133
U2 - 10.1007/s12035-016-0337-x
DO - 10.1007/s12035-016-0337-x
M3 - Article
SN - 0893-7648
VL - 54
SP - 6634
EP - 6646
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 8
ER -