15464
2012
eng
323
330
11
article
The Chromosome 9-ALS/FTD Consortium; The French research network on FTLD/FTLD/ALS
1
2017-11-07
--
--
Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
Background
We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Methods
We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion.
Findings
In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years.
Interpretation
A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.
The Lancet Neurology
10.1016/S1474-4422(12)70043-1
22406228
urn:nbn:de:bvb:20-opus-154644
The Lancet Neurology 2012; 11:323-330. DOI: 10.1016/S1474-4422(12)70043-1
259867
Elisa Majounie
Alan E. Renton
Kin Mok
Elise G. P. Dopper
Adrian Waite
Sara Rollinson
Adriano Chiò
Gabriella Restagno
Nayia Nicolaou
Javier Simon-Sanchez
John C. van Swieten
Yevgeniya Abramzon
Janel O. Johnson
Michael Sendtner
Roger Pamphlett
Richard W. Orrell
Simon Mead
Katie C. Sidle
Henry Houlden
Jonathan D. Rohrer
Karen E. Morrison
Hardev Pall
Kevin Talbot
Olaf Ansorge
Dena G. Hernandez
Sampath Arepalli
Mario Sabatelli
Gabriele Mora
Massimo Corbo
Fabio Giannini
Andrea Calvo
Elisabet Englund
Giuseppe Borghero
Gian Luca Floris
Anne M. Remes
Hannu Laaksovirta
Leo McCluskey
John Q. Trojanowski
Vivianna M. Van Deerlin
Gerard D. Schellenberg
Michael A. Nalls
Vivian E. Drory
Chin-Song Lu
Tu-Hsueh Yeh
Hiroyuki Ishiura
Yuji Takahashi
Shoji Tsuji
Isabelle Le Ber
Alexis Brice
Carsten Drepper
Nigel Williams
Janine Kirby
Pamela Shaw
John Hardy
Pentti J. Tienari
Peter Heutink
Huw R. Morris
Stuart Pickering-Brown
Bryan J. Traynor
eng
uncontrolled
DNA repeat expansion
eng
uncontrolled
C9orf72
eng
uncontrolled
amyotrophic lateral sclerosis
eng
uncontrolled
frontotemporal dementia
eng
uncontrolled
cross-sectional studies
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/15464/05_Majounie_Lancet.pdf
12095
2014
eng
3410-20
12
13
article
1
2015-10-26
--
--
Deep Proteomic Evaluation of Primary and Cell Line Motoneuron Disease Models Delineates Major Differences in Neuronal Characteristics*
The fatal neurodegenerative disorders amyotrophic lateral sclerosis and spinal muscular atrophy are, respectively, the most common motoneuron disease and genetic cause of infant death. Various in vitro model systems have been established to investigate motoneuron disease mechanisms, in particular immortalized cell lines and primary neurons. Using quantitative mass-spectrometry-based proteomics, we compared the proteomes of primary motoneurons to motoneuron-like cell lines NSC-34 and N2a, as well as to non-neuronal control cells, at a depth of 10,000 proteins. We used this resource to evaluate the suitability of murine in vitro model systems for cell biological and biochemical analysis of motoneuron disease mechanisms. Individual protein and pathway analysis indicated substantial differences between motoneuron-like cell lines and primary motoneurons, especially for proteins involved in differentiation, cytoskeleton, and receptor signaling, whereas common metabolic pathways were more similar. The proteins associated with amyotrophic lateral sclerosis also showed distinct differences between cell lines and primary motoneurons, providing a molecular basis for understanding fundamental alterations between cell lines and neurons with respect to neuronal pathways with relevance for disease mechanisms. Our study provides a proteomics resource for motoneuron research and presents a paradigm of how mass-spectrometry-based proteomics can be used to evaluate disease model systems.
Molecular & Cellular Proteomics : MCP
10.1074/mcp.M113.037291
1535-9484
25193168
urn:nbn:de:bvb:20-opus-120954
This research was originally published in Molecular & Cellular Proteomics. Daniel Hornburg, Carsten Drepper, Falk Butter, Felix Meissner, Michael Sendtner, and Matthias Mann. Deep Proteomic Evaluation of Primary and Cell Line Motoneuron Disease Models Delineates Major Differences in Neuronal Characteristics*. Molecular & Cellular Proteomics. 2014; 13:3410–3420. © the American Society for Biochemistry and Molecular Biology.
Molecular & Cellular Proteomics 13: 10.1074/mcp.M113.037291, 3410–3420, 2014.
259867
Daniel Hornburg
Carsten Drepper
Falk Butter
Felix Meissner
Michael Sendtner
Matthias Mann
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12095/014_Hornburg_Molecular_&_Cellular_Proteomics.pdf
26568
2021
eng
12284-12305
21
49
article
1
2022-04-05
--
--
Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin
Neurons critically rely on the functions of RNA-binding proteins to maintain their polarity and resistance to neurotoxic stress. HnRNP R has a diverse range of post-transcriptional regulatory functions and is important for neuronal development by regulating axon growth. Hnrnpr pre-mRNA undergoes alternative splicing giving rise to a full-length protein and a shorter isoform lacking its N-terminal acidic domain. To investigate functions selectively associated with the full-length hnRNP R isoform, we generated a Hnrnpr knockout mouse (Hnrnpr\(^{tm1a/tm1a}\)) in which expression of full-length hnRNP R was abolished while production of the truncated hnRNP R isoform was retained. Motoneurons cultured from Hnrnpr\(^{tm1a/tm1a}\) mice did not show any axonal growth defects but exhibited enhanced accumulation of double-strand breaks and an impaired DNA damage response upon exposure to genotoxic agents. Proteomic analysis of the hnRNP R interactome revealed the multifunctional protein Yb1 as a top interactor. Yb1-depleted motoneurons were defective in DNA damage repair. We show that Yb1 is recruited to chromatin upon DNA damage where it interacts with gamma-H2AX, a mechanism that is dependent on full-length hnRNP R. Our findings thus suggest a novel role of hnRNP R in maintaining genomic integrity and highlight the function of its N-terminal acidic domain in this context.
Nucleic Acids Research
10.1093/nar/gkab1120
urn:nbn:de:bvb:20-opus-265687
publish
Nucleic Acids Research (2021) 49:21, 12284-12305.https://doi.org/10.1093/nar/gkab1120
312325
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Hanaa Ghanawi
Luisa Hennlein
Abdolhossein Zare
Jakob Bader
Saeede Salehi
Daniel Hornburg
Changhe Ji
Rajeeve Sivadasan
Carsten Drepper
Felix Meissner
Matthias Mann
Sibylle Jablonka
Michael Briese
Michael Sendtner
eng
uncontrolled
nuclear ribonucleoprotein-R
eng
uncontrolled
determining gene-product
eng
uncontrolled
actin messenger RNA
eng
uncontrolled
comet assay
eng
uncontrolled
genome wide
eng
uncontrolled
spinal cord
eng
uncontrolled
YB-1
eng
uncontrolled
SMN
eng
uncontrolled
interacts
eng
uncontrolled
enrichment
Biowissenschaften; Biologie
Medizin und Gesundheit
open_access
Institut für Klinische Neurobiologie
OpenAIRE
Förderzeitraum 2021
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/26568/gkab1120.pdf
15456
2015
eng
373
387
130
article
1
2017-11-06
--
--
Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy
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.
Acta Neuropathologica
10.1007/s00401-015-1446-8
urn:nbn:de:bvb:20-opus-154569
Acta Neuropathologica (2015) 130:373–387. DOI: 10.1007/s00401-015-1446-8
259867
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Christian M. Simon
Stefanie Rauskolb
Jennifer M. Gunnersen
Bettina Holtmann
Carsten Drepper
Benjamin Dombert
Massimiliano Braga
Stefan Wiese
Sibylle Jablonka
Dirk Pühringer
Jürgen Zielasek
Andreas Hoeflich
Vincenzo Silani
Eckhard Wolf
Susanne Kneitz
Claudia Sommer
Klaus V. Toyka
Michael Sendtner
eng
uncontrolled
Motor nerve biopsy
eng
uncontrolled
Diabetic polyneuropathy
eng
uncontrolled
Neuropathy
eng
uncontrolled
Neurotrophic factors
eng
uncontrolled
Axonal degeneration
Medizin und Gesundheit
open_access
Frauenklinik und Poliklinik
Neurologische Klinik und Poliklinik
Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Theodor-Boveri-Institut für Biowissenschaften
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/15456/01_Simon_Acta.pdf
20179
2019
eng
199
12
article
1
2020-03-16
--
--
Transcript analysis of zebrafish GLUT3 genes, slc2a3a and slc2a3b, define overlapping as well as distinct expression domains in the zebrafish (Danio rerio) central nervous system
The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo. GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington’s and Alzheimer’s diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish (Danio rerio) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b. Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a. Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders.
Frontiers in Molecular Neuroscience
10.3389/fnmol.2019.00199
urn:nbn:de:bvb:20-opus-201797
Frontiers in Molecular Neuroscience 2019, 12:199. doi: 10.3389/fnmol.2019.00199
602805
728018
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Carina G. Lechermeier
Frederic Zimmer
Teresa M. Lüffe
Klaus-Peter Lesch
Marcel Romanos
Christina Lillesaar
Carsten Drepper
eng
uncontrolled
glucose transporter
eng
uncontrolled
nervous system
eng
uncontrolled
brain disorders
eng
uncontrolled
psychiatric disorders
eng
uncontrolled
brain development
eng
uncontrolled
GABA
eng
uncontrolled
GAD1
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie
Theodor-Boveri-Institut für Biowissenschaften
Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie
Förderzeitraum 2019
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/20179/Lechermeier_fnmol-12-00199.pdf
26471
2021
eng
11
article
1
2022-03-29
--
--
Increased locomotor activity via regulation of GABAergic signalling in foxp2 mutant zebrafish – implications for neurodevelopmental disorders
Recent advances in the genetics of neurodevelopmental disorders (NDDs) have identified the transcription factor FOXP2 as one of numerous risk genes, e.g. in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). FOXP2 function is suggested to be involved in GABAergic signalling and numerous studies demonstrate that GABAergic function is altered in NDDs, thus disrupting the excitation/inhibition balance. Interestingly, GABAergic signalling components, including glutamate-decarboxylase 1 (Gad1) and GABA receptors, are putative transcriptional targets of FOXP2. However, the specific role of FOXP2 in the pathomechanism of NDDs remains elusive. Here we test the hypothesis that Foxp2 affects behavioural dimensions via GABAergic signalling using zebrafish as model organism. We demonstrate that foxp2 is expressed by a subset of GABAergic neurons located in brain regions involved in motor functions, including the subpallium, posterior tuberculum, thalamus and medulla oblongata. Using CRISPR/Cas9 gene-editing we generated a novel foxp2 zebrafish loss-of-function mutant that exhibits increased locomotor activity. Further, genetic and/or pharmacological disruption of Gad1 or GABA-A receptors causes increased locomotor activity, resembling the phenotype of foxp2 mutants. Application of muscimol, a GABA-A receptor agonist, rescues the hyperactive phenotype induced by the foxp2 loss-of-function. By reverse translation of the therapeutic effect on hyperactive behaviour exerted by methylphenidate, we note that application of methylphenidate evokes different responses in wildtype compared to foxp2 or gad1b loss-of-function animals. Together, our findings support the hypothesis that foxp2 regulates locomotor activity via GABAergic signalling. This provides one targetable mechanism, which may contribute to behavioural phenotypes commonly observed in NDDs.
Translational Psychiatry
10.1038/s41398-021-01651-w
urn:nbn:de:bvb:20-opus-264713
publish
Translational Psychiatry (2021) 11:529. https://doi.org/10.1038/s41398-021-01651-w
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Teresa M. Lüffe
Andrea D'Orazio
Moritz Bauer
Zoi Gioga
Victoria Schoeffler
Klaus-Peter Lesch
Marcel Romanos
Carsten Drepper
Christina Lillesaar
eng
uncontrolled
comparative genomics
eng
uncontrolled
molecular neuroscience
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie
Lehrstuhl für Molekulare Psychiatrie
Förderzeitraum 2021
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/26471/s41398-021-01651-w.pdf
27742
2022
eng
15
article
1
--
2022-06-13
--
Loss-of-Function Models of the Metabotropic Glutamate Receptor Genes Grm8a and Grm8b Display Distinct Behavioral Phenotypes in Zebrafish Larvae (Danio rerio)
Members of the family of metabotropic glutamate receptors are involved in the pathomechanism of several disorders of the nervous system. Besides the well-investigated function of dysfunctional glutamate receptor signaling in neurodegenerative diseases, neurodevelopmental disorders (NDD), like autism spectrum disorders (ASD) and attention-deficit and hyperactivity disorder (ADHD) might also be partly caused by disturbed glutamate signaling during development. However, the underlying mechanism of the type III metabotropic glutamate receptor 8 (mGluR8 or GRM8) involvement in neurodevelopment and disease mechanism is largely unknown. Here we show that the expression pattern of the two orthologs of human GRM8, grm8a and grm8b, have evolved partially distinct expression patterns in the brain of zebrafish (Danio rerio), especially at adult stages, suggesting sub-functionalization of these two genes during evolution. Using double in situ hybridization staining in the developing brain we demonstrate that grm8a is expressed in a subset of gad1a-positive cells, pointing towards glutamatergic modulation of GABAergic signaling. Building on this result we generated loss-of-function models of both genes using CRISPR/Cas9. Both mutant lines are viable and display no obvious gross morphological phenotypes making them suitable for further analysis. Initial behavioral characterization revealed distinct phenotypes in larvae. Whereas grm8a mutant animals display reduced swimming velocity, grm8b mutant animals show increased thigmotaxis behavior, suggesting an anxiety-like phenotype. We anticipate that our two novel metabotropic glutamate receptor 8 zebrafish models may contribute to a deeper understanding of its function in normal development and its role in the pathomechanism of disorders of the central nervous system.
Frontiers in Molecular Neuroscience
1662-5099
10.3389/fnmol.2022.901309
urn:nbn:de:bvb:20-opus-277429
2022-06-27T08:16:51+00:00
sword
swordwue
attachment; filename=deposit.zip
6f85a020cc609d1d7ca72c4792f93147
Frontiers in Molecular Neuroscience (2022) 15:901309. DOI:10.3389/fnmol.2022.901309
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Teresa M. Lüffe
Moritz Bauer
Zoi Gioga
Duru Özbay
Marcel Romanos
Christina Lillesaar
Carsten Drepper
eng
uncontrolled
nervous system
eng
uncontrolled
brain disorders
eng
uncontrolled
psychiatric disorders
eng
uncontrolled
brain development
eng
uncontrolled
excitatory/inhibitory imbalance
eng
uncontrolled
metabotropic glutamate (mGlu) receptor
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie
Import
Förderzeitraum 2022
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/27742/Data_Sheet_1.PDF
https://opus.bibliothek.uni-wuerzburg.de/files/27742/fnmol-15-901309.pdf