TITLE

Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients

AUTHOR(S)
Robicsek, O; Karry, R; Petit, I; Salman-Kesner, N; Müller, F-J; Klein, E; Aberdam, D; Ben-Shachar, D
PUB. DATE
October 2013
SOURCE
Molecular Psychiatry;Oct2013, Vol. 18 Issue 10, p1067
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
One of the prevailing hypotheses suggests schizophrenia as a neurodevelopmental disorder, involving dysfunction of dopaminergic and glutamatergic systems. Accumulating evidence suggests mitochondria as an additional pathological factor in schizophrenia. An attractive model to study processes related to neurodevelopment in schizophrenia is reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) and differentiating them into different neuronal lineages. iPSCs from three schizophrenia patients and from two controls were reprogrammed from hair follicle keratinocytes, because of their accessibility and common ectodermal origin with neurons. iPSCs were differentiated into Pax6+/Nestin+ neural precursors and then further differentiated into β3-Tubulin+/tyrosine hydroxylase+/DAT+ dopaminergic neurons. In addition, iPSCs were differentiated through embryonic bodies into β3-Tubulin+/Tbox brain1+ glutamatergic neurons. Schizophrenia-derived dopaminergic cells showed severely impaired ability to differentiate, whereas glutamatergic cells were unable to maturate. Mitochondrial respiration and its sensitivity to dopamine-induced inhibition were impaired in schizophrenia-derived keratinocytes and iPSCs. Moreover, we observed dissipation of mitochondrial membrane potential (Δψm) and perturbations in mitochondrial network structure and connectivity in dopaminergic along the differentiation process and in glutamatergic cells. Our data unravel perturbations in neural differentiation and mitochondrial function, which may be interconnected, and of relevance to dysfunctional neurodevelopmental processes in schizophrenia.
ACCESSION #
90360787

 

Related Articles

  • Patient-specific induced pluripotent stem cells in neurological disease modeling: the importance of nonhuman primate models. Zhifang Qiu; Farnsworth, Steven L.; Mishra, Anuja; Hornsby, Peter J. // Stem Cells & Cloning: Advances & Applications;2013, Vol. 6, p19 

    The development of the technology for derivation of induced pluripotent stem (iPS) cells from human patients and animal models has opened up new pathways to the better understanding of many human diseases, and has created new opportunities for therapeutic approaches. Here, we consider one...

  • iPS models of Parkin and PINK1. Rakovic, Aleksandar; Seibler, Philip; Klein, Christine // Biochemical Society Transactions;Apr2015, Vol. 43 Issue 2, p302 

    Parkinson disease (PD) is a degenerative disorder of the central nervous system resulting from depletion of dopaminergic neurons and currently remains incurable despite enormous international research efforts. The development of induced pluripotent stem cell (iPSC) technology opened up the...

  • Comparison of Human Primary with Human iPS Cell-Derived Dopaminergic Neuron Grafts in the Rat Model for Parkinson's Disease. Peng, Su-Ping; Copray, Sjef // Stem Cell Reviews & Reports;Feb2016, Vol. 12 Issue 1, p105 

    Neuronal degeneration within the substantia nigra and the loss of the dopaminergic nigro-striatal pathway are the major hallmarks of Parkinson's disease (PD). Grafts of foetal ventral mesencephalic (VM) dopaminergic (DA) neurons into the striatum have been shown to be able to restore striatal...

  • Cellular reprogramming: a new approach to modelling Parkinson's disease. Hartfield, Elizabeth M.; Fernandes, Hugo J. R.; Vowles, Jane; Cowley, Sally A.; Wade-Martins, Richard // Biochemical Society Transactions;Oct2012, Vol. 40 Issue 5, p1152 

    iPSCs (induced pluripotent stem cells) offer an unparalleled opportunity to generate and study physiologically relevant cell types in culture. iPSCs can be generated by reprogramming almost any somatic cell type using pluripotency factors such as Oct4, S0X2, Nanog and Klf4. By reprogramming...

  • Induced Pluripotent Stem Cell Technology and Direct Conversion: New Possibilities to Study and Treat Parkinson's Disease. Roessler, Reinhard; Boddeke, Erik; Copray, Sjef // Stem Cell Reviews & Reports;Aug2013, Vol. 9 Issue 4, p505 

    Recent developments in in vitro disease modeling and regenerative medicine have placed induced pluripotent stem cells (iPSCs) in the center of attention as a unique source to study Parkinson's disease. After only 5 years of intensive research, human iPSCs can be generated without viral...

  • MicroRNA Profiling of Neurons Generated Using Induced Pluripotent Stem Cells Derived from Patients with Schizophrenia and Schizoaffective Disorder, and 22q11.2 Del. Zhao, Dejian; Lin, Mingyan; Chen, Jian; Pedrosa, Erika; Hrabovsky, Anastasia; Fourcade, H. Matthew; Zheng, Deyou; Lachman, Herbert M. // PLoS ONE;7/14/2015, Vol. 10 Issue 7, p1 

    We are using induced pluripotent stem cell (iPSC) technology to study neuropsychiatric disorders associated with 22q11.2 microdeletions (del), the most common known schizophrenia (SZ)-associated genetic factor. Several genes in the region have been implicated; a promising candidate is DGCR8,...

  • Synaptic dysregulation in a human iPS cell model of mental disorders. Wen, Zhexing; Yoritomo, Nadine; Kaibuchi, Kozo; Zou, Jizhong; Cheng, Linzhao; Ross, Christopher A.; Margolis, Russell L.; Chen, Gong; Song, Hongjun; Ming, Guo-li; Nguyen, Ha Nam; Guo, Ziyuan; Lalli, Matthew A.; Guzman, Elmer; Kosik, Kenneth S.; Wang, Xinyuan; Su, Yijing; Kim, Nam-Shik; Yoon, Ki-Jun; Zhang, Ce // Nature;11/20/2014, Vol. 515 Issue 7527, p414 

    Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and 'a disease of synapses' is the major hypothesis for the biological basis of schizophrenia. Although this hypothesis has gained indirect support from...

  • Enhancing Induced Pluripotent Stem CellModels of Schizophrenia. Wright, Rebecca; Réthelyi, János M.; Gage, Fred H. // JAMA Psychiatry;Mar2014, Vol. 71 Issue 3, p334 

    The article discusses issues related to enhancing induced pluripotent stem cell (IPSC) models of schizophrenia. It cites several ways to enhance future IPSC models of schizophrenia to reduce variability between studies. It also examines the generation of specific, homogeneous neuronal...

  • MeCP2 Regulates the Synaptic Expression of a Dysbindin-BLOC-1 Network Component in Mouse Brain and Human Induced Pluripotent Stem Cell-Derived Neurons. Larimore, Jennifer; Ryder, Pearl V.; Kim, Kun-Yong; Ambrose, L. Alex; Chapleau, Christopher; Calfa, Gaston; Gross, Christina; Bassell, Gary J.; Pozzo-Miller, Lucas; Smith, Yoland; Talbot, Konrad; Park, In-Hyun; Faundez, Victor // PLoS ONE;Jun2013, Vol. 8 Issue 6, p1 

    Clinical, epidemiological, and genetic evidence suggest overlapping pathogenic mechanisms between autism spectrum disorder (ASD) and schizophrenia. We tested this hypothesis by asking if mutations in the ASD gene MECP2 which cause Rett syndrome affect the expression of genes encoding the...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics