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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.

SUBMITTER: Murray A

PROVIDER: S-EPMC4737213 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Brief report: isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration.

Murray Aoife A Letourneau Audrey A Canzonetta Claudia C Stathaki Elisavet E Gimelli Stefania S Sloan-Bena Frederique F Abrehart Robert R Goh Pollyanna P Lim Shuhui S Baldo Chiara C Dagna-Bricarelli Franca F Hannan Saad S Mortensen Martin M Ballard David D Syndercombe Court Denise D Fusaki Noemi N Hasegawa Mamoru M Smart Trevor G TG Bishop Cleo C Antonarakis Stylianos E SE Groet Jürgen J Nizetic Dean D

Stem cells (Dayton, Ohio) 20150601 6

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 iden ...[more]

PMID: 25694335

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Project description:Down syndrome, which results from a trisomic imbalance for chromosome 21, has been associated with 80+ phenotypic traits. However, the cellular changes that arise in somatic cells due to this aneuploid condition are not fully understood. The primary aim of this study was to determine if germline trisomy 21 is associated with an increase in spontaneous somatic cell chromosomal instability frequencies (SCINF). To achieve this aim, we quantified SCINF in people with mosaic Down syndrome using a cytokinesis-blocked micronucleus assay. By comparing values in their isogenic trisomic/disomic cells, we obtained a measure of differences in SCINF that are directly attributable to a trisomy 21 imbalance, since differential effects attributable to "background" genetic factors and environmental exposures could be eliminated. A cross-sectional assessment of 69 people with mosaic Down syndrome (ages 1 to 44; mean age of 12.84 years) showed a significantly higher frequency of micronuclei in their trisomic (0.37 ± 0.35 [mean ± standard deviation]) compared to disomic cells (0.18 ± 0.11)(P <0.0001). The daughter binucleates also showed significantly higher levels of abnormal patterns in the trisomic (1.68 ± 1.21) compared to disomic (0.35 ± 0.45) cells (P <0.0001). Moreover, a significant Age x Cell Type interaction was noted (P = 0.0113), indicating the relationship between age and SCINF differed between the trisomic and disomic cells. Similarly, a longitudinal assessment (mean time interval of 3.9 years; range of 2 to 6 years) of 18 participants showed a mean 1.63-fold increase in SCINF within individuals over time for their trisomic cells (P = 0.0186), compared to a 1.13-fold change in their disomic cells (P = 0.0464). In summary, these results showed a trisomy 21-associated, age-related increase in SCINF. They also underscore the strength of the isogenic mosaic Down syndrome model system for "unmasking" cellular changes arising from a trisomy 21 imbalance.

Dataset Information

Brief report: isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration.

Publications

Brief report: isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration.

Similar Datasets

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