title: Tetrahydrocarbazoles decrease elevated SOCE in medium spiny neurons from transgenic YAC128 mice, a model of Huntington's disease.
abstract: Huntington's disease (HD) is a hereditary neurodegenerative disease caused by a polyglutamine expansion within the huntingtin (HTT) gene. One of the cellular functions that is dysregulated in HD is store-operated calcium entry (SOCE), a process in which the depletion of Ca2+from the endoplasmic reticulum (ER) induces Ca2+influx from the extracellular space. We detected an enhanced activity of SOC channels in medium spiny neurons (MSNs) from YAC128 mice, a transgenic model of HD, and investigated whether this could be reverted by tetrahydrocarbazoles. The compound 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride was indeed able to restore the disturbed Ca2+homeostasis and stabilize SOCE in YAC128 MSN cultures. We also detected a beneficial effect of this compound on the mitochondrial membrane potential. Since dysregulated Ca2+homeostasis is believed to be one of the pathological hallmarks of HD, this compound might be a lead structure for HD treatment.
authors.affiliation: Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, Trojdena 4, 02-109, Warsaw, Poland. Electronic address: mczeredys@iimcb.gov.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Czeredys
authors.affiliation: Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, Trojdena 4, 02-109, Warsaw, Poland.
authors.forename: Filip
authors.initials: F
authors.lastname: Maciag
authors.affiliation: Department of Neurology, University Medical Center and Focus Program Translational Neuroscience (FTN) of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, D-55131, Mainz, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Methner
authors.affiliation: Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, Trojdena 4, 02-109, Warsaw, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Kuznicki
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D003470:Culture Media; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006706:Homeostasis; D017136:Ion Transport; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002227:Carbazoles; D003470:Culture Media; D002118:Calcium
keywords: Huntingtin; Huntington's disease; Medium spiny neurons; Store-operated calcium entry; Tetrahydrocarbazoles; YAC128