TY  - JOUR
A1  - Palladino, Viola Stella
A1  - Chiocchetti, Andreas G.
A1  - Frank, Lukas
A1  - Haslinger, Denise
A1  - McNeill, Rhiannon
A1  - Radtke, Franziska
A1  - Till, Andreas
A1  - Haupt, Simone
A1  - Brüstle, Oliver
A1  - Günther, Katharina
A1  - Edenhofer, Frank
A1  - Hoffmann, Per
A1  - Reif, Andreas
A1  - Kittel-Schneider, Sarah
T1  - Energy metabolism disturbances in cell models of PARK2 CNV carriers with ADHD
JF  - Journal of Clinical Medicine
N2  - The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.
KW  - ADHD
KW  - hiPSC
KW  - PARK2
KW  - mitochondria
KW  - disease modelling
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220074
SN  - 2077-0383
VL  - 9
IS  - 12
ER  - 
TY  - JOUR
A1  - Ahmad, Ruhel
A1  - Wolber, Wanja
A1  - Eckardt, Sigrid
A1  - Koch, Philipp
A1  - Schmitt, Jessica
A1  - Semechkin, Ruslan
A1  - Geis, Christian
A1  - Heckmann, Manfred
A1  - Brüstle, Oliver
A1  - McLaughlin, John K.
A1  - Sirén, Anna-Leena
A1  - Müller, Albrecht M.
T1  - Functional Neuronal Cells Generated by Human Parthenogenetic Stem Cells
JF  - PLoS One
N2  - Parent of origin imprints on the genome have been implicated in the regulation of neural cell type differentiation. The ability of human parthenogenetic (PG) embryonic stem cells (hpESCs) to undergo neural lineage and cell type-specific differentiation is undefined. We determined the potential of hpESCs to differentiate into various neural subtypes. Concurrently, we examined DNA methylation and expression status of imprinted genes. Under culture conditions promoting neural differentiation, hpESC-derived neural stem cells (hpNSCs) gave rise to glia and neuron-like cells that expressed subtype-specific markers and generated action potentials. Analysis of imprinting in hpESCs and in hpNSCs revealed that maternal-specific gene expression patterns and imprinting marks were generally maintained in PG cells upon differentiation. Our results demonstrate that despite the lack of a paternal genome, hpESCs generate proliferating NSCs that are capable of differentiation into physiologically functional neuron-like cells and maintain allele-specific expression of imprinted genes. Thus, hpESCs can serve as a model to study the role of maternal and paternal genomes in neural development and to better understand imprinting-associated brain diseases.
KW  - methylation
KW  - derivation
KW  - blastocysts
KW  - pluripotent
KW  - differentiation
KW  - lines
KW  - brain development
KW  - in-vitro
KW  - mice
KW  - specification
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130268
VL  - 7
IS  - 8
ER  -