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Human embryonic stem cell models of Huntington disease

Journal Article


Abstract


  • Huntington disease (HD) is an incurable late-onset neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the HD gene (HTT). The major hallmark of disease pathology is neurodegeneration in the brain. Currently, there are no useful in-vitro human models of HD. Recently, two human embryonic stem cell (hESC) lines carrying partial (CAG37) and fully (CAG51) penetrant mutant alleles have been derived from affected IVF embryos identified following preimplantation genetic diagnosis (PGD). Fluorescence polymerase chain reaction (F-PCR) and Genescan analysis confirmed the original embryonic HD genotypes. Reverse transcription PCR (RT-PCR) analysis confirmed the expression of mutant transcripts and western blot analysis demonstrated expression of mutant huntingtin protein (HTT). After treatment with noggin, HD hESC formed neurospheres, which could be further differentiated into cells susceptible to neurodegeneration in HD, namely primary neurones and astrocytes. Small pool PCR analysis of neurosphere cells revealed instability of disease-length CAG repeats following differentiation. The presence of active HTT genes, neural differentiation capabilities and evidence of CAG repeat instability indicates these HD hESC lines may serve as valuable in-vitro human models of HD to better understand the mechanisms of neurodegeneration in patients, and for drug screening to identify new therapies for human clinical trials.

Publication Date


  • 2009

Citation


  • Niclis, J. C., Trounson, A. O., Dottori, M., Ellisdon, A. M., Bottomley, S. P., Verlinsky, Y., & Cram, D. S. (2009). Human embryonic stem cell models of Huntington disease. Reproductive BioMedicine Online, 19(1), 106-113. doi:10.1016/S1472-6483(10)60053-3

Scopus Eid


  • 2-s2.0-68149162402

Start Page


  • 106

End Page


  • 113

Volume


  • 19

Issue


  • 1

Abstract


  • Huntington disease (HD) is an incurable late-onset neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the HD gene (HTT). The major hallmark of disease pathology is neurodegeneration in the brain. Currently, there are no useful in-vitro human models of HD. Recently, two human embryonic stem cell (hESC) lines carrying partial (CAG37) and fully (CAG51) penetrant mutant alleles have been derived from affected IVF embryos identified following preimplantation genetic diagnosis (PGD). Fluorescence polymerase chain reaction (F-PCR) and Genescan analysis confirmed the original embryonic HD genotypes. Reverse transcription PCR (RT-PCR) analysis confirmed the expression of mutant transcripts and western blot analysis demonstrated expression of mutant huntingtin protein (HTT). After treatment with noggin, HD hESC formed neurospheres, which could be further differentiated into cells susceptible to neurodegeneration in HD, namely primary neurones and astrocytes. Small pool PCR analysis of neurosphere cells revealed instability of disease-length CAG repeats following differentiation. The presence of active HTT genes, neural differentiation capabilities and evidence of CAG repeat instability indicates these HD hESC lines may serve as valuable in-vitro human models of HD to better understand the mechanisms of neurodegeneration in patients, and for drug screening to identify new therapies for human clinical trials.

Publication Date


  • 2009

Citation


  • Niclis, J. C., Trounson, A. O., Dottori, M., Ellisdon, A. M., Bottomley, S. P., Verlinsky, Y., & Cram, D. S. (2009). Human embryonic stem cell models of Huntington disease. Reproductive BioMedicine Online, 19(1), 106-113. doi:10.1016/S1472-6483(10)60053-3

Scopus Eid


  • 2-s2.0-68149162402

Start Page


  • 106

End Page


  • 113

Volume


  • 19

Issue


  • 1