title: Brief report: isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration.
abstract: Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer, and other important common diseases. New drugs could be identified and disease mechanisms better understood by establishment of well-controlled cell model systems. We have developed a first nonintegration-reprogrammed isogenic human induced pluripotent stem cell (iPSC) model of DS by reprogramming the skin fibroblasts from an adult individual with constitutional mosaicism for DS and separately cloning multiple isogenic T21 and euploid (D21) iPSC lines. Our model shows a very low number of reprogramming rearrangements as assessed by a high-resolution whole genome CGH-array hybridization, and it reproduces several cellular pathologies seen in primary human DS cells, as assessed by automated high-content microscopic analysis. Early differentiation shows an imbalance of the lineage-specific stem/progenitor cell compartments: T21 causes slower proliferation of neural and faster expansion of hematopoietic lineage. T21 iPSC-derived neurons show increased production of amyloid peptide-containing material, a decrease in mitochondrial membrane potential, and an increased number and abnormal appearance of mitochondria. Finally, T21-derived neurons show significantly higher number of DNA double-strand breaks than isogenic D21 controls. Our fully isogenic system therefore opens possibilities for modeling mechanisms of developmental, accelerated ageing, and neurodegenerative pathologies caused by T21.
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine, London, United Kingdom.|The LonDownS Consortium, Wellcome Trust, London, United Kingdom.
authors.forename: Aoife
authors.initials: A
authors.lastname: Murray
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Letourneau
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine, London, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Canzonetta
authors.affiliation: Service of Genetic Medicine, University Geneva Hospitals, Geneva, Switzerland.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Stathaki
authors.affiliation: Service of Genetic Medicine, University Geneva Hospitals, Geneva, Switzerland.
authors.forename: Stefania
authors.initials: S
authors.lastname: Gimelli
authors.affiliation: Service of Genetic Medicine, University Geneva Hospitals, Geneva, Switzerland.
authors.forename: Frederique
authors.initials: F
authors.lastname: Sloan-Bena
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine, London, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Abrehart
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine, London, United Kingdom.|The LonDownS Consortium, Wellcome Trust, London, United Kingdom.
authors.forename: Pollyanna
authors.initials: P
authors.lastname: Goh
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Lim
authors.affiliation: Human Genetics Laboratory, Galliera Hospital, Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Baldo
authors.affiliation: Liguria Department of Genetics, Genoa, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Dagna-Bricarelli
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors.forename: Saad
authors.initials: S
authors.lastname: Hannan
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Mortensen
authors.affiliation: Department of Forensic and Analytical Science, King's College, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Ballard
authors.affiliation: Department of Forensic and Analytical Science, King's College, London, United Kingdom.
authors.forename: Denise
authors.initials: D
authors.lastname: Syndercombe Court
authors.affiliation: Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Noemi
authors.initials: N
authors.lastname: Fusaki
authors.affiliation: DNAVEC Corporation, Ibaraki, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine, London, United Kingdom.
authors.forename: Cleo
authors.initials: C
authors.lastname: Bishop
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine, London, United Kingdom.|Stem Cell Laboratory, National Centre for Bowel Research and Surgical Innovation, Queen Mary University of London, London, United Kingdom.|The LonDownS Consortium, Wellcome Trust, London, United Kingdom.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Groet
authors.affiliation: The Blizard Institute, Barts and The London School of Medicine, London, United Kingdom.|The LonDownS Consortium, Wellcome Trust, London, United Kingdom.|Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
authors.forename: Dean
authors.initials: D
authors.lastname: Nizetic
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004314:Down Syndrome / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008928:Mitochondria / Q000235:genetics; D009474:Neurons / Q000166:cytology*
keywords: Down syndrome; Neurodegeneration; Neurogenesis; Neuronal differentiation