Neurobiology of Disease (Apr 2012)

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

  • Stefano Camnasio,
  • Alessia Delli Carri,
  • Angelo Lombardo,
  • Iwona Grad,
  • Caterina Mariotti,
  • Alessia Castucci,
  • Björn Rozell,
  • Pietro Lo Riso,
  • Valentina Castiglioni,
  • Chiara Zuccato,
  • Christelle Rochon,
  • Yasuhiro Takashima,
  • Giuseppe Diaferia,
  • Ida Biunno,
  • Cinzia Gellera,
  • Marisa Jaconi,
  • Austin Smith,
  • Outi Hovatta,
  • Luigi Naldini,
  • Stefano Di Donato,
  • Anis Feki,
  • Elena Cattaneo

Journal volume & issue
Vol. 46, no. 1
pp. 41 – 51


Read online

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.