HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity

Virginia B. Mattis, Colton Tom, Sergey Akimov, Jasmine Saeedian, Michael E. Østergaard, Amber L. Southwell, Crystal N. Doty, Loren Ornelas, Anais Sahabian, Lindsay Lenaeus, Berhan Mandefro, Dhruv Sareen, Jamshid Arjomand, Michael R. Hayden, Christopher A. Ross, Clive N. Svendsen

Research output: Contribution to journalArticle

Abstract

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. TheHDiPSC Consortium has recently reported a newin 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. Itwas 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 theNMDAbut also mGlu andAMPA/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.

Original languageEnglish (US)
Pages (from-to)3257-3271
Number of pages15
JournalHuman molecular genetics
Volume24
Issue number11
DOIs
StatePublished - Dec 15 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Mattis, V. B., Tom, C., Akimov, S., Saeedian, J., Østergaard, M. E., Southwell, A. L., Doty, C. N., Ornelas, L., Sahabian, A., Lenaeus, L., Mandefro, B., Sareen, D., Arjomand, J., Hayden, M. R., Ross, C. A., & Svendsen, C. N. (2014). HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity. Human molecular genetics, 24(11), 3257-3271. https://doi.org/10.1093/hmg/ddv080