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Characterization of forebrain neurons derived from late-onset Huntington's disease human embryonic stem cell lines

Journal Article


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Abstract


  • Huntington's disease (HD) is an incurable neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the Huntingtin (HTT) gene. Recently, induced pluripotent stem cell (iPSC) lines carrying atypical and aggressive (CAG60+) HD variants have been generated and exhibit disparate molecular pathologies. Here we investigate two human embryonic stem ce ll (hESC) lines carrying CAG 37 and CAG 51 typical late-onset repeat expansions in comparison to wildtype control lines during undifferentiated states and throughout forebrain neuronal differentiation. Pluripotent HD lines demonstrate growth, viability, pluripotent gene expression, mitochondrial activity and forebrain specification that is indistinguishable from control lines. Expression profiles of crucial genes known to be dysregulated in HD remain unperturbed in the presence of mutant protein and throughout differentiation; however, elevated glutamate-evoked responses were observed in HD CAG 51 neurons. These findings suggest typical late-onset HD mutations do not alter pluripotent parameters or the capacity to generate forebrain neurons, but that such progeny may recapitulate hallmarks observed in established HD model systems. Such HD models will help further our understanding of the cascade of pathological events leading to disease onset and progression, while simultaneously facilitating the identification of candidate HD therapeutics.

Authors


  •   Niclis, Jonathan C. (external author)
  •   Pinar, Anita (external author)
  •   Haynes, John (external author)
  •   Alsanie, Walaa (external author)
  •   Jenny, Robert (external author)
  •   Dottori, Mirella
  •   Cram, David (external author)

Publication Date


  • 2013

Citation


  • Niclis, J. C., Pinar, A., Haynes, J. M., Alsanie, W., Jenny, R., Dottori, M. & Cram, D. S. (2013). Characterization of forebrain neurons derived from late-onset Huntington's disease human embryonic stem cell lines. Frontiers in Cellular Neuroscience, 7 (APR), 37-1-37-13.

Scopus Eid


  • 2-s2.0-84875984674

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2192&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1165

Has Global Citation Frequency


Start Page


  • 37-1

End Page


  • 37-13

Volume


  • 7

Issue


  • APR

Place Of Publication


  • Switzerland

Abstract


  • Huntington's disease (HD) is an incurable neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the Huntingtin (HTT) gene. Recently, induced pluripotent stem cell (iPSC) lines carrying atypical and aggressive (CAG60+) HD variants have been generated and exhibit disparate molecular pathologies. Here we investigate two human embryonic stem ce ll (hESC) lines carrying CAG 37 and CAG 51 typical late-onset repeat expansions in comparison to wildtype control lines during undifferentiated states and throughout forebrain neuronal differentiation. Pluripotent HD lines demonstrate growth, viability, pluripotent gene expression, mitochondrial activity and forebrain specification that is indistinguishable from control lines. Expression profiles of crucial genes known to be dysregulated in HD remain unperturbed in the presence of mutant protein and throughout differentiation; however, elevated glutamate-evoked responses were observed in HD CAG 51 neurons. These findings suggest typical late-onset HD mutations do not alter pluripotent parameters or the capacity to generate forebrain neurons, but that such progeny may recapitulate hallmarks observed in established HD model systems. Such HD models will help further our understanding of the cascade of pathological events leading to disease onset and progression, while simultaneously facilitating the identification of candidate HD therapeutics.

Authors


  •   Niclis, Jonathan C. (external author)
  •   Pinar, Anita (external author)
  •   Haynes, John (external author)
  •   Alsanie, Walaa (external author)
  •   Jenny, Robert (external author)
  •   Dottori, Mirella
  •   Cram, David (external author)

Publication Date


  • 2013

Citation


  • Niclis, J. C., Pinar, A., Haynes, J. M., Alsanie, W., Jenny, R., Dottori, M. & Cram, D. S. (2013). Characterization of forebrain neurons derived from late-onset Huntington's disease human embryonic stem cell lines. Frontiers in Cellular Neuroscience, 7 (APR), 37-1-37-13.

Scopus Eid


  • 2-s2.0-84875984674

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2192&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1165

Has Global Citation Frequency


Start Page


  • 37-1

End Page


  • 37-13

Volume


  • 7

Issue


  • APR

Place Of Publication


  • Switzerland