Brief Report: Isogenic Induced Pluripotent Stem Cell Lines From an Adult With Mosaic Down Syndrome Model Accelerated Neuronal Ageing and Neurodegeneration

摘要: Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS beginning to yield pharmaceutical therapeutic interventions for amelioration disability, which are currently being tested in clinical trials. also a unique system investigation pathological protective mechanisms accelerated ageing, neurodegeneration, dementia, cancer, other important diseases. New drugs could be identified disease better understood by establishment well-controlled cell model systems. We have developed first nonintegration-reprogrammed isogenic human induced pluripotent stem (iPSC) reprogramming skin fibroblasts from an adult individual with constitutional mosaicism separately cloning multiple T21 euploid (D21) iPSC lines. Our shows very low number rearrangements as assessed high-resolution whole genome CGH-array hybridization, it reproduces several cellular pathologies seen primary cells, automated high-content microscopic analysis. Early differentiation imbalance lineage-specific stem/progenitor compartments: causes slower proliferation neural faster expansion hematopoietic lineage. iPSC-derived neurons show increased production amyloid peptide-containing material, decrease mitochondrial membrane potential, abnormal appearance mitochondria. Finally, T21-derived significantly higher DNA double-strand breaks than D21 controls. fully therefore opens possibilities modeling developmental, neurodegenerative caused T21.