BackgroundHuntington’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.ResultsHere, 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.ConclusionsOur 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.
Manifestation of Huntington’s disease pathology in human induced pluripotent stem cell-derived neurons
E. Nekrasov,V. Vigont,S. Klyushnikov,O. Lebedeva,E. Vassina,A. Bogomazova,I. V. Chestkov,T. Semashko,E. Kiseleva,Lyubov A. Suldina,P. A. Bobrovsky,O. Zimina,M. Ryazantseva,A. Skopin,S. Illarioshkin,E. Kaznacheyeva,M. Lagarkova,S. Kiselev
Published 2016 in Molecular Neurodegeneration
ABSTRACT
PUBLICATION RECORD
- Publication year
2016
- Venue
Molecular Neurodegeneration
- Publication date
2016-04-14
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- cag repeat expansion
The expanded trinucleotide repeat in exon 1 of the huntingtin gene associated with Huntington’s disease in the patient lines used here.
Aliases: CAG expansion
- calcium entry
Calcium influx into neurons assessed as a functional readout of store-operated signaling.
Aliases: Ca2+ entry
- cell aging
The culture-aging condition used to assess later-onset neuronal vulnerability and treatment effects.
Aliases: aging
- evp4593
A quinazoline derivative compound tested on the Huntington’s disease neurons for its effects on cellular phenotypes.
Aliases: quinazoline derivative
- gaba ms-like neurons
Neurons differentiated in culture to resemble striatal GABAergic medium spiny neurons.
Aliases: GMSLNs, GABAergic medium spiny-like neurons
- induced pluripotent stem cells
Reprogrammed human stem cells generated from patient samples and used as the starting material for neuronal differentiation in this work.
Aliases: iPSCs
- lysosomes/autophagosomes
Intracellular degradative vesicular compartments monitored as markers of altered cellular processing in the neurons.
Aliases: lysosomes, autophagosomes
- mutant huntingtin protein
The disease-associated huntingtin protein encoded by the expanded-repeat allele and measured for aggregation in the differentiated neurons.
Aliases: mHTT
- nuclear indentations
Abnormal indentations of the nuclear envelope observed as a morphological feature in the cultured neurons.
Aliases: nuclear morphology changes
- store-operated channel currents
Calcium-entry-associated membrane currents measured in the differentiated neurons as part of the electrophysiological phenotype.
Aliases: SOC currents
REFERENCES
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