The first reported generation of several induced pluripotent stem cell lines from homozygous and heterozygous Huntington's disease patients demonstrates mutation related enhanced lysosomal activity

Neurobiol Dis. 2012 Apr;46(1):41-51. doi: 10.1016/j.nbd.2011.12.042.


Neuronal disorders, like Huntington's disease (HD), are difficult to study, due to limited cell accessibility, late onset manifestations, and low availability of material. The establishment of an in vitro model that recapitulates features of the disease may help understanding the cellular and molecular events that trigger disease manifestations. Here, we describe the generation and characterization of a series of induced pluripotent stem (iPS) cells derived from patients with HD, including two rare homozygous genotypes and one heterozygous genotype. We used lentiviral technology to transfer key genes for inducing reprogramming. To confirm pluripotency and differentiation of iPS cells, we used PCR amplification and immunocytochemistry to measure the expression of marker genes in embryoid bodies and neurons. We also analyzed teratomas that formed in iPS cell-injected mice. We found that the length of the pathological CAG repeat did not increase during reprogramming, after long term growth in vitro, and after differentiation into neurons. In addition, we observed no differences between normal and mutant genotypes in reprogramming, growth rate, caspase activation or neuronal differentiation. However, we observed a significant increase in lysosomal activity in HD-iPS cells compared to control iPS cells, both during self-renewal and in iPS-derived neurons. In conclusion, we have established stable HD-iPS cell lines that can be used for investigating disease mechanisms that underlie HD. The CAG stability and lysosomal activity represent novel observations in HD-iPS cells. In the future, these cells may provide the basis for a powerful platform for drug screening and target identification in HD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Culture Techniques / methods*
  • Cell Line
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Heterozygote
  • Homozygote
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Lysosomes / genetics*
  • Lysosomes / metabolism
  • Mice
  • Mice, SCID
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Phenotype
  • Pluripotent Stem Cells / metabolism*
  • Teratoma / genetics
  • Teratoma / metabolism
  • Transcriptional Activation / physiology


  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins