PMID- 25740845 OWN - NLM STAT- MEDLINE DCOM- 20160216 LR - 20181113 IS - 1460-2083 (Electronic) IS - 0964-6906 (Print) IS - 0964-6906 (Linking) VI - 24 IP - 11 DP - 2015 Jun 1 TI - HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity. PG - 3257-71 LID - 10.1093/hmg/ddv080 [doi] AB - Huntington's disease (HD) is a fatal neurodegenerative disease, caused by expansion of polyglutamine repeats in the Huntingtin gene, with longer expansions leading to earlier ages of onset. The HD iPSC Consortium has recently reported a new in vitro model of HD based on the generation of induced pluripotent stem cells (iPSCs) from HD patients and controls. The current study has furthered the disease in a dish model of HD by generating new non-integrating HD and control iPSC lines. Both HD and control iPSC lines can be efficiently differentiated into neurons/glia; however, the HD-derived cells maintained a significantly greater number of nestin-expressing neural progenitor cells compared with control cells. This cell population showed enhanced vulnerability to brain-derived neurotrophic factor (BDNF) withdrawal in the juvenile-onset HD (JHD) lines, which appeared to be CAG repeat-dependent and mediated by the loss of signaling from the TrkB receptor. It was postulated that this increased death following BDNF withdrawal may be due to glutamate toxicity, as the N-methyl-d-aspartate (NMDA) receptor subunit NR2B was up-regulated in the cultures. Indeed, blocking glutamate signaling, not just through the NMDA but also mGlu and AMPA/Kainate receptors, completely reversed the cell death phenotype. This study suggests that the pathogenesis of JHD may involve in part a population of 'persistent' neural progenitors that are selectively vulnerable to BDNF withdrawal. Similar results were seen in adult hippocampal-derived neural progenitors isolated from the BACHD model mouse. Together, these results provide important insight into HD mechanisms at early developmental time points, which may suggest novel approaches to HD therapeutics. CI - (c) The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Mattis, Virginia B AU - Mattis VB AD - The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA. FAU - Tom, Colton AU - Tom C AD - The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA. FAU - Akimov, Sergey AU - Akimov S AD - Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Saeedian, Jasmine AU - Saeedian J AD - The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA. FAU - Ostergaard, Michael E AU - Ostergaard ME AD - ISIS Pharmaceuticals, Carlsbad, CA, USA. FAU - Southwell, Amber L AU - Southwell AL AD - Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada and. FAU - Doty, Crystal N AU - Doty CN AD - Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada and. FAU - Ornelas, Loren AU - Ornelas L AD - The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA. FAU - Sahabian, Anais AU - Sahabian A AD - The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA. FAU - Lenaeus, Lindsay AU - Lenaeus L AD - The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA. FAU - Mandefro, Berhan AU - Mandefro B AD - The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA. FAU - Sareen, Dhruv AU - Sareen D AD - The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA. FAU - Arjomand, Jamshid AU - Arjomand J AD - CHDI Foundation, Princeton, NJ, USA. FAU - Hayden, Michael R AU - Hayden MR AD - Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada and. FAU - Ross, Christopher A AU - Ross CA AD - Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Svendsen, Clive N AU - Svendsen CN AD - The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA clive.svendsen@cshs.org. LA - eng GR - R01 NS076631/NS/NINDS NIH HHS/United States GR - NS078370/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150303 PL - England TA - Hum Mol Genet JT - Human molecular genetics JID - 9208958 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 3KX376GY7L (Glutamic Acid) RN - 7171WSG8A2 (BDNF protein, human) SB - IM MH - Age of Onset MH - Animals MH - Apoptosis MH - Brain-Derived Neurotrophic Factor/*physiology MH - Cell Survival MH - Cells, Cultured MH - Glutamic Acid/*physiology MH - Humans MH - Huntington Disease/*metabolism/pathology MH - Induced Pluripotent Stem Cells/*metabolism MH - Mice MH - Neural Stem Cells/*physiology PMC - PMC4424959 EDAT- 2015/03/06 06:00 MHDA- 2016/02/18 06:00 PMCR- 2016/06/01 CRDT- 2015/03/06 06:00 PHST- 2014/10/27 00:00 [received] PHST- 2015/03/02 00:00 [accepted] PHST- 2015/03/06 06:00 [entrez] PHST- 2015/03/06 06:00 [pubmed] PHST- 2016/02/18 06:00 [medline] PHST- 2016/06/01 00:00 [pmc-release] AID - ddv080 [pii] AID - 10.1093/hmg/ddv080 [doi] PST - ppublish SO - Hum Mol Genet. 2015 Jun 1;24(11):3257-71. doi: 10.1093/hmg/ddv080. Epub 2015 Mar 3.