title: Manifestation of Huntington's disease pathology in human induced pluripotent stem cell-derived neurons.
abstract: BACKGROUND
  Huntington's disease (HD) is an incurable hereditary neurodegenerative disorder, which manifests itself as a loss of GABAergic medium spiny (GABA MS) neurons in the striatum and caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. There is no cure for HD, existing pharmaceutical can only relieve its symptoms.
  
  
  RESULTS
  Here, induced pluripotent stem cells were established from patients with low CAG repeat expansion in the huntingtin gene, and were then efficiently differentiated into GABA MS-like neurons (GMSLNs) under defined culture conditions. The generated HD GMSLNs recapitulated disease pathology in vitro, as evidenced by mutant huntingtin protein aggregation, increased number of lysosomes/autophagosomes, nuclear indentations, and enhanced neuronal death during cell aging. Moreover, store-operated channel (SOC) currents were detected in the differentiated neurons, and enhanced calcium entry was reproducibly demonstrated in all HD GMSLNs genotypes. Additionally, the quinazoline derivative, EVP4593, reduced the number of lysosomes/autophagosomes and SOC currents in HD GMSLNs and exerted neuroprotective effects during cell aging.
  
  
  CONCLUSIONS
  Our data is the first to demonstrate the direct link of nuclear morphology and SOC calcium deregulation to mutant huntingtin protein expression in iPSCs-derived neurons with disease-mimetic hallmarks, providing a valuable tool for identification of candidate anti-HD drugs. Our experiments demonstrated that EVP4593 may be a promising anti-HD drug.
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119333, Russia.
authors.forename: Evgeny D
authors.initials: ED
authors.lastname: Nekrasov
authors.affiliation: Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Vigont
authors.affiliation: Research Center of Neurology, Moscow, 125367, Russia.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Klyushnikov
authors.affiliation: Scientific-Research Institute of Physical-Chemical Medicine, Moscow, 119435, Russia.
authors.forename: Olga S
authors.initials: OS
authors.lastname: Lebedeva
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119333, Russia.
authors.forename: Ekaterina M
authors.initials: EM
authors.lastname: Vassina
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119333, Russia.
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Bogomazova
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119333, Russia.
authors.forename: Ilya V
authors.initials: IV
authors.lastname: Chestkov
authors.affiliation: Scientific-Research Institute of Physical-Chemical Medicine, Moscow, 119435, Russia.
authors.forename: Tatiana A
authors.initials: TA
authors.lastname: Semashko
authors.affiliation: Federal Research Center Institute of Cytology and Genetics SB RAS, Novosibirsk, 630090, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Kiseleva
authors.affiliation: Federal Research Center Institute of Cytology and Genetics SB RAS, Novosibirsk, 630090, Russia.
authors.forename: Lyubov A
authors.initials: LA
authors.lastname: Suldina
authors.affiliation: Scientific-Research Institute of Physical-Chemical Medicine, Moscow, 119435, Russia.
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Bobrovsky
authors.affiliation: Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Zimina
authors.affiliation: Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Ryazantseva
authors.affiliation: Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia.
authors.forename: Anton Yu
authors.initials: AY
authors.lastname: Skopin
authors.affiliation: Research Center of Neurology, Moscow, 125367, Russia.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Illarioshkin
authors.affiliation: Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Kaznacheyeva
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119333, Russia.|Scientific-Research Institute of Physical-Chemical Medicine, Moscow, 119435, Russia.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Lagarkova
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119333, Russia. kiselev@vigg.ru.|Kazan State University, Kazan, 420008, Russia. kiselev@vigg.ru.
authors.forename: Sergey L
authors.initials: SL
authors.lastname: Kiselev
mesh_terms: D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D003342:Corpus Striatum / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008247:Lysosomes / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D009687:Nuclear Proteins / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D009687:Nuclear Proteins; D002118:Calcium
keywords: Aging; Differentiation; GABAergic medium spiny neurons; Human induced pluripotent stem cells; Huntington’s disease; Neurodegeneration; Neuroprotection; Nuclear indentations; Store-operated calcium entry