HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity.
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.
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA.
Virginia B
VB
Mattis
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA.
Colton
C
Tom
Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sergey
S
Akimov
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA.
Jasmine
J
Saeedian
ISIS Pharmaceuticals, Carlsbad, CA, USA.
Michael E
ME
Østergaard
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada and.
Amber L
AL
Southwell
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada and.
Crystal N
CN
Doty
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA.
Loren
L
Ornelas
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA.
Anais
A
Sahabian
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA.
Lindsay
L
Lenaeus
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA.
Berhan
B
Mandefro
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8400 AHSP, Los Angeles, CA 90048, USA.
Dhruv
D
Sareen
CHDI Foundation, Princeton, NJ, USA.
Jamshid
J
Arjomand
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada and.
Michael R
MR
Hayden
Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Christopher A
CA
Ross
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.
Clive N
CN
Svendsen
D017668:Age of Onset; D000818:Animals; D017209:Apoptosis; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000502:physiology*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D051379:Mice; D058953:Neural Stem Cells / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D018698:Glutamic Acid; C579455:BDNF protein, human