Induced pluripotent stem cell lines from Huntington's disease mice undergo neuronal differentiation while showing alterations in the lysosomal pathway.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an excessive expansion of a CAG trinucleotide repeat in the gene encoding the protein huntingtin, resulting in an elongated stretch of glutamines near the N-terminus of the protein. Here we report the derivation of a collection of 11 induced pluripotent stem (iPS) cell lines generated through somatic reprogramming of fibroblasts obtained from the R6/2 transgenic HD mouse line. We show that CAG expansion has no effect on reprogramming efficiency, cell proliferation rate, brain-derived neurotrophic factor level, or neurogenic potential. However, genes involved in the cholesterol biosynthesis pathway, which is altered in HD, are also affected in HD-iPS cell lines. Furthermore, we found a lysosomal gene upregulation and an increase in lysosome number in HD-iPS cell lines. These observations suggest that iPS cells from HD mice replicate some but not all of the molecular phenotypes typically observed in the disease; additionally, they do not manifest increased cell death propensity either under self-renewal or differentiated conditions. More studies will be necessary to transform a revolutionary technology into a powerful platform for drug screening approaches.
Department of Pharmacological Sciences and Centre for Stem Cell Research, Università degli Studi di Milano, Via Balzaretti 9-20133 Milano, Italy.
Valentina
V
Castiglioni
Marco
M
Onorati
Christelle
C
Rochon
Elena
E
Cattaneo
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D004195:Disease Models, Animal; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000201:enzymology*; D008247:Lysosomes / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009434:Neural Pathways / Q000166:cytology / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins