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Frontiers in Biology

Front Biol    2012, Vol. 7 Issue (3) : 179-188
Application of reprogrammed patient cells to investigate the etiology of neurological and psychiatric disorders
Kimberly M. CHRISTIAN1,2(), Hongjun SONG1,2,3, Guo-li MING1,2,3
1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; 2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; 3. The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Cellular reprogramming allows for the de novo generation of human neurons and glial cells from patients with neurological and psychiatric disorders. Crucially, this technology preserves the genome of the donor individual and thus provides a unique opportunity for systematic investigation of genetic influences on neuronal pathophysiology. Although direct reprogramming of adult somatic cells to neurons is now possible, the majority of recent studies have used induced pluripotent stem cells (iPSCs) derived from patient fibroblasts to generate neural progenitors that can be differentiated to specific neural cell types. Investigations of monogenic diseases have established proof-of-principle for many aspects of cellular disease modeling, including targeted differentiation of neuronal populations and rescue of phenotypes in patient iPSC lines. Refinement of protocols to allow for efficient generation of iPSC lines from large patient cohorts may reveal common functional pathology and genetic interactions in diseases with a polygenic basis. We review several recent studies that illustrate the utility of iPSC-based cellular models of neurodevelopmental and neurodegenerative disorders to identify novel phenotypes and therapeutic approaches.

Keywords reprogramming      iPSCs      neurodevelopment      neurodegeneration     
Corresponding Author(s): CHRISTIAN Kimberly M.,   
Issue Date: 01 June 2012
 Cite this article:   
Hongjun SONG,Guo-li MING,Kimberly M. CHRISTIAN. Application of reprogrammed patient cells to investigate the etiology of neurological and psychiatric disorders[J]. Front Biol, 2012, 7(3): 179-188.
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Hongjun SONG
Guo-li MING
Fig.1  Simplified schematic diagram showing the development of cell-based assays for the investigation of neurological disease mechanisms.
(Blue-shaded box) Using fibroblasts obtained from patients and disease-free control subjects, human neurons can be generated through direct conversion or following an intervening stage of pluripotency. Disease-relevant neuronal populations can be enriched during the differentiation process through targeted protocols. (Pink-shaded box) Phenotypic analysis of human neurons generated from patients and control subjects may include any cell-based morphological or functional assay (e.g. dendritic development, synaptogenesis, synaptic connectivity, electrophysiology, intracellular signaling) as well as genetic and epigenetic profiling to produce complete transcriptomes and methylomes of homogenous populations. High-throughput approaches are particularly desirable for polygenic diseases to identify common functional disruptions across a heterogeneous patient population. (Yellow shaded box) Based on information acquired during the phenotypic screens or from previous investigations, targeted genetic manipulation can repair known mutations, which can then be subjected to phenotypic screens or introduced to neural progenitor populations to track development following genetic repair. Bioactive compounds can be similarly screened at various timepoints to evaluate potential to reverse or prevent phenotypic abnormalities. (Green-shaded box) Transplantation of patient-derived neural progenitors to mice can provide critical information regarding development and degeneration. Ultimately, cell-based screening and repair of neuronal dysfunction can be used to develop novel therapeutics for the patient population.
RTTMeCP2missense, nonsense and frameshift mutationsGABAergic and glutamatergic neuronsReduced soma size, number of spines, glutamatergic synapses; altered Ca2+ transients, sEPSCs, sIPSCsIGF1 - partial increase in synapse number; Gentamycin - restored MeCP2 expression in nonsense mutationMarchetto et al., 2010
TSCACNA1C point mutationLayer-specific cortical neuronsDifferential gene expression; TH expression~Pa?ca et al., 2011
FDIKBKAP point mutationCNS and PNS precursorsIKBKAP splicing, neurogenesis, migration of neural crest precursorsKinetin rescue of splicing and autonomic neuron differentiationLee et al., 2009
SZ4bp deletion in DISC1- frameshift mutation~~~Chiang et al, 2011
SZNot knownGlutamatergic, GABAergic and dopaminergic neuronsDecreased neuronal connectivity, increased NRG1 expressionLoxapine rescue of neuronal connectivity deficits, NRG1 expressionBrennand et al., 2011
PDLRRK2dominant missense mutationMidbrain dopaminergic neuronsDifferential gene expression; increased α-synuclein expression, increased susceptibility to H2O2, 6-OHDA, and MG-132~Nguyen et al., 2011
PDPINK1 nonsense or missense mutationsDopaminergic neuronsImpaired stress-induced translocation of Parkin to mitochondria; increased PGC-1α and mtDNA following depolarizationOverexpression of WT PINK1 restored translocation capacity and prevented PGC-1α increaseSeibler et al., 2011
PDPARKINexon deletion(3 and/or 5)Midbrain dopaminergic neuronsIncreased spontaneous dopamine release; enhanced transcription of MAO-A, MAO-B; increased oxidative stressOverexpression of WT-parkin rescued all phenotypesJiang et al., 2012
PDα synuclein point mutationDopaminergic neurons~ZFN gene-editing; repair of point mutation in patient iPSCs; introduction of point mutation in hESCsSoldner et al., 2011
ADAPP duplication in 2 patients (APPDp);No identified mutations in 2 sporadic AD patients (sAD)Glutamatergic, GABAergic and cholinergic neuronsIncreased amyloid-β, p-tau, and aGSK-3β expression in both APPDp lines and 1 of 2 sAD linesPartial rescue of amyloid-β, p-tau, and aGSK-3β expression with γ and β-secretase inhibitorsIsrael et al., 2012
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