TY - JOUR A1 - Majounie, Elisa A1 - Renton, Alan E. A1 - Mok, Kin A1 - Dopper, Elise G. P. A1 - Waite, Adrian A1 - Rollinson, Sara A1 - Chiò, Adriano A1 - Restagno, Gabriella A1 - Nicolaou, Nayia A1 - Simon-Sanchez, Javier A1 - van Swieten, John C. A1 - Abramzon, Yevgeniya A1 - Johnson, Janel O. A1 - Sendtner, Michael A1 - Pamphlett, Roger A1 - Orrell, Richard W. A1 - Mead, Simon A1 - Sidle, Katie C. A1 - Houlden, Henry A1 - Rohrer, Jonathan D. A1 - Morrison, Karen E. A1 - Pall, Hardev A1 - Talbot, Kevin A1 - Ansorge, Olaf A1 - Hernandez, Dena G. A1 - Arepalli, Sampath A1 - Sabatelli, Mario A1 - Mora, Gabriele A1 - Corbo, Massimo A1 - Giannini, Fabio A1 - Calvo, Andrea A1 - Englund, Elisabet A1 - Borghero, Giuseppe A1 - Floris, Gian Luca A1 - Remes, Anne M. A1 - Laaksovirta, Hannu A1 - McCluskey, Leo A1 - Trojanowski, John Q. A1 - Van Deerlin, Vivianna M. A1 - Schellenberg, Gerard D. A1 - Nalls, Michael A. A1 - Drory, Vivian E. A1 - Lu, Chin-Song A1 - Yeh, Tu-Hsueh A1 - Ishiura, Hiroyuki A1 - Takahashi, Yuji A1 - Tsuji, Shoji A1 - Le Ber, Isabelle A1 - Brice, Alexis A1 - Drepper, Carsten A1 - Williams, Nigel A1 - Kirby, Janine A1 - Shaw, Pamela A1 - Hardy, John A1 - Tienari, Pentti J. A1 - Heutink, Peter A1 - Morris, Huw R. A1 - Pickering-Brown, Stuart A1 - Traynor, Bryan J. T1 - Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study JF - The Lancet Neurology N2 - 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. KW - DNA repeat expansion KW - C9orf72 KW - amyotrophic lateral sclerosis KW - frontotemporal dementia KW - cross-sectional studies Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154644 VL - 11 SP - 323 EP - 330 ER - TY - JOUR A1 - Hornburg, Daniel A1 - Drepper, Carsten A1 - Butter, Falk A1 - Meissner, Felix A1 - Sendtner, Michael A1 - Mann, Matthias T1 - Deep Proteomic Evaluation of Primary and Cell Line Motoneuron Disease Models Delineates Major Differences in Neuronal Characteristics* JF - Molecular & Cellular Proteomics : MCP N2 - 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. Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120954 SN - 1535-9484 N1 - 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. VL - 13 IS - 12 ER - 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 -