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Manifestation of Huntington's disease pathology in human induced pluripotent stem cell-derived neurons.

ABSTRACT: 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.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.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.

SUBMITTER: Nekrasov ED

PROVIDER: S-EPMC4832474 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Manifestation of Huntington's disease pathology in human induced pluripotent stem cell-derived neurons.

Nekrasov Evgeny D ED Vigont Vladimir A VA Klyushnikov Sergey A SA Lebedeva Olga S OS Vassina Ekaterina M EM Bogomazova Alexandra N AN Chestkov Ilya V IV Semashko Tatiana A TA Kiseleva Elena E Kiseleva Elena E Suldina Lyubov A LA Bobrovsky Pavel A PA Zimina Olga A OA Ryazantseva Maria A MA Skopin Anton Yu AY Illarioshkin Sergey N SN Kaznacheyeva Elena V EV Lagarkova Maria A MA Kiselev Sergey L SL

Molecular neurodegeneration 20160414

<h4>Background</h4>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.<h4>Results</h4>Here, induced pluripotent stem cells were established from patients with low CAG repeat expansion in the huntingtin gene, and were th ...[more]

PMID: 27080129

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Project description:OBJECTIVES:Alzheimer's disease (AD) is the most common neurodegenerative disease which is characterized by the formation of amyloid beta (A?) plaques and neurofibrillary tangles. These abnormal proteins induce disturbance in mitochondrial dynamics and defect in autophagy system. Since presenilin-1 (PS1) is a core component in ?-secretase complex, the mutations of PS1 gene cause the interference of ?-secretase activity and lead to the increased A?42 secretion. We aimed to characterize the patient-specific induced pluripotent stem cell (iPSC) line carrying PS1-S170F mutation. Furthermore, we tested whether disease-modifying drug can reduce AD pathology in the AD iPSC-derived neurons. MATERIALS AND METHODS:Mononuclear cells (MNCs) were isolated freshly from the peripheral blood of an autosomal dominant AD (ADAD) patient carrying presenilin-1 (PS1) mutation (Ser170Phe; PS1-S170F) and a cognitively normal control. We generated induced pluripotent stem cell (iPSC) lines, which were differentiated into functional cortical neurons. Then, we measured the markers indicative of AD pathogenesis using immunocytochemistry and Western blot. We also investigated the mitochondrial dynamics in the AD iPSC-derived neurons using Mito-tracker. RESULTS:We observed that both extracellular and intracellular A? levels were dramatically increased in the PS1-S170F iPSC-derived neurons, compared with the control iPSC-derived neurons. Furthermore, PS1-S170F iPSC-derived neurons showed high expression levels of p-Tau, which were detected both in the soma and neurites. The mitochondrial velocity in the PS1-S170F iPSC-derived neurons was much reduced, compared with that of the control. We also found a significant decrease of fusion-related protein Mfn1 (membrane proteins mitofusin 1) and an increase of fission-related protein DRP1 (dynamin-related protein 1) in the PS1-S170F iPSC-derived neurons. We further observed the defects of autophagy-related clearance in the PS1-S170F iPSC-derived neurons. Finally, we demonstrated the levels of A? and p-Tau can be dramatically reduced by the treatment of LY-2886721, a BACE1 inhibitor. CONCLUSIONS:Taken together, we have established and characterized the pathological features of an AD patient carrying PS1-S170F mutation using iPSC technology, which will be the first case on this mutation and this iPSC line will serve as a useful resource for studying AD pathogenesis and drug screening in the future.

Dataset Information

Manifestation of Huntington's disease pathology in human induced pluripotent stem cell-derived neurons.

Publications

Manifestation of Huntington's disease pathology in human induced pluripotent stem cell-derived neurons.

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