Huntington’s disease (HD) is an autosomal dominant disorder caused by expansion of polyglutamine (CAG) repeats in the Huntingtin gene, leading to loss of striatal and cortical neurons and deficits in coordinated movements and cognition. Transgenic rodent models are valuable for testing cell death mechanisms and therapeutic intervention. However, mouse and rat models may not fully represent the human condition. Induced pluripotent stem (iPS) cells, which show striking similarities to embryonic stem cells, can now be derived from human adult somatic tissues and have the capacity to be lineage restricted into various neuronal subtypes. More importantly, recent studies have been successful in generating patient specific iPS cells from a variety of diseases including amyotrophic lateral sclerosis, spinal muscular atrophy, Parkinson’s disease, and HD. Using lentiviral mediated over-expression of Oct4, Sox2, Nanog, Lin28, cMyc and Klf4, we successfully generated iPS cell lines from three fibroblast samples: (1) from a 6 year old affected male with 180 CAG repeats, (2) from a 29 year old affected female with 60 CAG repeats, and (3) from a 21 year old unaffected female with 33 CAG repeats. We have generated striatal neurons from these three lines in order to determine the affect CAG repeat length has on neuronal health and survival. In order to accelerate these studies a consortium of researchers has been formed who are currently assessing the phenotype of neurons generated from these iPS lines. Studies are ongoing amongst the consortium members in order to establish a CAGdependent HD phenotype in these lines.
EFFECT OF MUTANT HUNTINGTIN ON STRIATAL NEURONS DIFFERENTIATED FROM HUNTINGTON’S DISEASE INDUCED PLURIPOTENT STEM CELLS
ONORATI, MARCO;
2011-01-01
Abstract
Huntington’s disease (HD) is an autosomal dominant disorder caused by expansion of polyglutamine (CAG) repeats in the Huntingtin gene, leading to loss of striatal and cortical neurons and deficits in coordinated movements and cognition. Transgenic rodent models are valuable for testing cell death mechanisms and therapeutic intervention. However, mouse and rat models may not fully represent the human condition. Induced pluripotent stem (iPS) cells, which show striking similarities to embryonic stem cells, can now be derived from human adult somatic tissues and have the capacity to be lineage restricted into various neuronal subtypes. More importantly, recent studies have been successful in generating patient specific iPS cells from a variety of diseases including amyotrophic lateral sclerosis, spinal muscular atrophy, Parkinson’s disease, and HD. Using lentiviral mediated over-expression of Oct4, Sox2, Nanog, Lin28, cMyc and Klf4, we successfully generated iPS cell lines from three fibroblast samples: (1) from a 6 year old affected male with 180 CAG repeats, (2) from a 29 year old affected female with 60 CAG repeats, and (3) from a 21 year old unaffected female with 33 CAG repeats. We have generated striatal neurons from these three lines in order to determine the affect CAG repeat length has on neuronal health and survival. In order to accelerate these studies a consortium of researchers has been formed who are currently assessing the phenotype of neurons generated from these iPS lines. Studies are ongoing amongst the consortium members in order to establish a CAGdependent HD phenotype in these lines.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
