TY  - JOUR
A1  - Mitjans, M.
A1  - Begemann, M.
A1  - Ju, A.
A1  - Dere, E.
A1  - Wüstefeld, L.
A1  - Hofer, S.
A1  - Hassouna, I.
A1  - Balkenhol, J.
A1  - Oliveira, B.
A1  - Van der Auwera, S.
A1  - Tammer, R.
A1  - Hammerschmidt, K.
A1  - Völzke, H.
A1  - Homuth, G.
A1  - Cecconi, F.
A1  - Chowdhury, K.
A1  - Grabe, H.
A1  - Frahm, J.
A1  - Boretius, S.
A1  - Dandekar, T.
A1  - Ehrenreich, H.
T1  - Sexual dimorphism of \(AMBRA1\)-related autistic features in human and mouse
JF  - Translational Psychiatry
N2  - \(Ambra1\) is linked to autophagy and neurodevelopment. Heterozygous \(Ambra1\) deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of \(AMBRA1\) for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal \(AMBRA1\) genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower \(AMBRA1\) mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by \(in\) \(silico\) analysis. Searching for further autism-relevant characteristics in \(Ambra1^{+/−}\) mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an \(in\) \(vivo\) readout of neuronal excitation–inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of \(AMBRA1/Ambra1\) partial loss-of-function genotypes for female autistic traits. Moreover, they suggest \(Ambra1\) heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.
KW  - biology
KW  - clinical genetics
KW  - molecular neuroscience
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173782
VL  - 2017
IS  - 7
ER  - 
TY  - JOUR
A1  - Hassouna, I.
A1  - Ott, C.
A1  - Wüstefeld, L.
A1  - Offen, N.
A1  - Neher, R. A.
A1  - Mitkovski, M.
A1  - Winkler, D.
A1  - Sperling, S.
A1  - Fries, L.
A1  - Goebbels, S.
A1  - Vreja, I. C.
A1  - Hagemeyer, N.
A1  - Dittrich, M.
A1  - Rossetti, M. F.
A1  - Kröhnert, K.
A1  - Hannke, K.
A1  - Boretius, S.
A1  - Zeug, A.
A1  - Höschen, C.
A1  - Dandekar, T.
A1  - Dere, E.
A1  - Neher, E.
A1  - Rizzoli, S. O.
A1  - Nave, K.-A.
A1  - Sirén, A.-L.
A1  - Ehrenreich, H.
T1  - Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus
JF  - Molecular Psychiatry
N2  - Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of similar to 20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a \(^{15}\)N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated \(^{15}\)N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration.
KW  - neural stem-cells
KW  - recombinat-human-erythropoietin
KW  - cognitive functions
KW  - pyramidal neurons
KW  - nervous-sytem
KW  - brain-injury
KW  - mouse-brain
KW  - progenitors
KW  - mice
KW  - memory
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186669
VL  - 21
IS  - 12
ER  - 
TY  - JOUR
A1  - Zirkel, J.
A1  - Cecil, A.
A1  - Schäfer, F.
A1  - Rahlfs, S.
A1  - Ouedraogo, A.
A1  - Xiao, K.
A1  - Sawadogo, S.
A1  - Coulibaly, B.
A1  - Becker, K.
A1  - Dandekar, T.
T1  - Analyzing Thiol-Dependent Redox Networks in the Presence of Methylene Blue and Other Antimalarial Agents with RT-PCR-Supported in silico Modeling
JF  - Bioinformatics and Biology Insights
N2  - BACKGROUND: In the face of growing resistance in malaria parasites to drugs, pharmacological combination therapies are important. There is accumulating evidence that methylene blue (MB) is an effective drug against malaria. Here we explore the biological effects of both MB alone and in combination therapy using modeling and experimental data.
RESULTS: We built a model of the central metabolic pathways in P. falciparum. Metabolic flux modes and their changes under MB were calculated by integrating experimental data (RT-PCR data on mRNAs for redox enzymes) as constraints and results from the YANA software package for metabolic pathway calculations. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, chloroquine resistance based on pfmdr/and pfcrt transporters, as well as pyrimethamine/sulfadoxine resistance (by mutations in DHF/DHPS), were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs.
CONCLUSIONS: Theoretical and experimental results support that methylene blue should, because of its resistance-breaking potential, be further tested as a key component in drug combination therapy efforts in holoendemic areas.
KW  - methylene blue
KW  - malaria
KW  - elementary mode analysis
KW  - drug
KW  - resistance
KW  - combination therapy
KW  - pathway
KW  - metabolic flux
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123751
N1  - This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.
VL  - 6
ER  -