TY  - JOUR
A1  - Simon, Christian M.
A1  - Rauskolb, Stefanie
A1  - Gunnersen, Jennifer M.
A1  - Holtmann, Bettina
A1  - Drepper, Carsten
A1  - Dombert, Benjamin
A1  - Braga, Massimiliano
A1  - Wiese, Stefan
A1  - Jablonka, Sibylle
A1  - Pühringer, Dirk
A1  - Zielasek, Jürgen
A1  - Hoeflich, Andreas
A1  - Silani, Vincenzo
A1  - Wolf, Eckhard
A1  - Kneitz, Susanne
A1  - Sommer, Claudia
A1  - Toyka, Klaus V.
A1  - Sendtner, Michael
T1  - Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy
JF  - Acta Neuropathologica
N2  - Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes.The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor(IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.
KW  - Motor nerve biopsy
KW  - Diabetic polyneuropathy
KW  - Neuropathy
KW  - Neurotrophic factors
KW  - Axonal degeneration
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154569
VL  - 130
SP  - 373
EP  - 387
ER  - 
TY  - JOUR
A1  - Schulz, Herbert
A1  - Ruppert, Ann-Kathrin
A1  - Herms, Stefan
A1  - Wolf, Christiane
A1  - Mirza-Schreiber, Nazanin
A1  - Stegle, Oliver
A1  - Czamara, Darina
A1  - Forstner, Andreas J.
A1  - Sivalingam, Sugirthan
A1  - Schoch, Susanne
A1  - Moebus, Susanne
A1  - Pütz, Benno
A1  - Hillmer, Axel
A1  - Fricker, Nadine
A1  - Vatter, Hartmut
A1  - Müller-Myhsok, Bertram
A1  - Nöthen, Markus M.
A1  - Becker, Albert J.
A1  - Hoffmann, Per
A1  - Sander, Thomas
A1  - Cichon, Sven
T1  - Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus
JF  - Nature Communications
N2  - Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the \(cis\)-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify \(cis\)-meQTLs at 14,118 CpG methylation sites and \(cis\)-eQTLs for 302 3′-mRNA transcripts of 288 genes. Hippocampal \(cis\)-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. \(Cis\)-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of \(cis\)-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders.
KW  - psychiatry
KW  - epigenetics in the nervous system
KW  - epigenomics
KW  - gene expression
KW  - neurological disorders
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173168
VL  - 8
ER  -