TY - JOUR A1 - Markert, Sebastian M. A1 - Skoruppa, Michael A1 - Yu, Bin A1 - Mulcahy, Ben A1 - Zhen, Mai A1 - Gao, Shangbang A1 - Sendtner, Michael A1 - Stigloher, Christian T1 - Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission JF - Biology Open N2 - The amyotrophic lateral sclerosis (ALS) neurodegenerative disorder has been associated with multiple genetic lesions, including mutations in the gene for fused in sarcoma (FUS), a nuclear-localized RNA/DNA-binding protein. Neuronal expression of the pathological form of FUS proteins in Caenorhabditis elegans results in mislocalization and aggregation of FUS in the cytoplasm, and leads to impairment of motility. However, the mechanisms by which the mutant FUS disrupts neuronal health and function remain unclear. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. We show that ectopic expression of wild-type or ALS-associated human FUS impairs synaptic vesicle docking at neuromuscular junctions. ALS-associated FUS led to the emergence of a population of large, electron-dense, and filament-filled endosomes. Electrophysiological recording revealed reduced transmission from motor neurons to muscles. Together, these results suggest a pathological effect of ALS-causing FUS at synaptic structure and function organization. KW - C. elegans KW - fused in sarcoma KW - amyotrophic lateral sclerosis KW - uper-resolution array tomography KW - electron tomography KW - neuromuscular junction Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230662 VL - 9 ER - TY - JOUR A1 - Briese, Michael A1 - Saal-Bauernschubert, Lena A1 - Lüningschrör, Patrick A1 - Moradi, Mehri A1 - Dombert, Benjamin A1 - Surrey, Verena A1 - Appenzeller, Silke A1 - Deng, Chunchu A1 - Jablonka, Sibylle A1 - Sendtner, Michael T1 - Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function JF - Acta Neuropathologica Communications N2 - Protein inclusions containing the RNA-binding protein TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis and other neurodegenerative disorders. The loss of TDP-43 function that is associated with these inclusions affects post-transcriptional processing of RNAs in multiple ways including pre-mRNA splicing, nucleocytoplasmic transport, modulation of mRNA stability and translation. In contrast, less is known about the role of TDP-43 in axonal RNA metabolism in motoneurons. Here we show that depletion of Tdp-43 in primary motoneurons affects axon growth. This defect is accompanied by subcellular transcriptome alterations in the axonal and somatodendritic compartment. The axonal localization of transcripts encoding components of the cytoskeleton, the translational machinery and transcripts involved in mitochondrial energy metabolism were particularly affected by loss of Tdp-43. Accordingly, we observed reduced protein synthesis and disturbed mitochondrial functions in axons of Tdp-43-depleted motoneurons. Treatment with nicotinamide rescued the axon growth defect associated with loss of Tdp-43. These results show that Tdp-43 depletion in motoneurons affects several pathways integral to axon health indicating that loss of TDP-43 function could thus make a major contribution to axonal pathomechanisms in ALS. KW - amyotrophic lateral sclerosis KW - Tdp-43 KW - axonal transcriptome KW - nicotinamide Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230322 VL - 8 ER - TY - JOUR A1 - Erlbeck, Helena A1 - Mochty, Ursula A1 - Kübler, Andrea A1 - Real, Ruben G. L. T1 - Circadian course of the P300 ERP in patients with amyotrophic lateral sclerosis - implications for brain-computer interfaces (BCI) JF - BMC Neurology N2 - Background: Accidents or neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) can lead to progressing, extensive, and complete paralysis leaving patients aware but unable to communicate (locked-in state). Brain-computer interfaces (BCI) based on electroencephalography represent an important approach to establish communication with these patients. The most common BCI for communication rely on the P300, a positive deflection arising in response to rare events. To foster broader application of BCIs for restoring lost function, also for end-users with impaired vision, we explored whether there were specific time windows during the day in which a P300 driven BCI should be preferably applied. Methods: The present study investigated the influence of time of the day and modality (visual vs. auditory) on P300 amplitude and latency. A sample of 14 patients (end-users) with ALS and 14 healthy age matched volunteers participated in the study and P300 event-related potentials (ERP) were recorded at four different times (10, 12 am, 2, & 4 pm) during the day. Results: Results indicated no differences in P300 amplitudes or latencies between groups (ALS patients v. healthy participants) or time of measurement. In the auditory condition, latencies were shorter and amplitudes smaller as compared to the visual condition. Conclusion: Our findings suggest applicability of EEG/BCI sessions in patients with ALS throughout normal waking hours. Future studies using actual BCI systems are needed to generalize these findings with regard to BCI effectiveness/efficiency and other times of day. KW - brain computer interface KW - amyotrophic lateral sclerosis KW - ALS KW - P300 KW - auditory KW - visual KW - BCI Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157423 VL - 17 IS - 3 ER - 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 - Halder, Sebastian A1 - Hammer, Eva Maria A1 - Kleih, Sonja Claudia A1 - Bogdan, Martin A1 - Rosenstiel, Wolfgang A1 - Birbaumer, Niels A1 - Kübler, Andrea T1 - Prediction of Auditory and Visual P300 Brain-Computer Interface Aptitude JF - PLoS ONE N2 - Objective Brain-computer interfaces (BCIs) provide a non-muscular communication channel for patients with late-stage motoneuron disease (e.g., amyotrophic lateral sclerosis (ALS)) or otherwise motor impaired people and are also used for motor rehabilitation in chronic stroke. Differences in the ability to use a BCI vary from person to person and from session to session. A reliable predictor of aptitude would allow for the selection of suitable BCI paradigms. For this reason, we investigated whether P300 BCI aptitude could be predicted from a short experiment with a standard auditory oddball. Methods Forty healthy participants performed an electroencephalography (EEG) based visual and auditory P300-BCI spelling task in a single session. In addition, prior to each session an auditory oddball was presented. Features extracted from the auditory oddball were analyzed with respect to predictive power for BCI aptitude. Results Correlation between auditory oddball response and P300 BCI accuracy revealed a strong relationship between accuracy and N2 amplitude and the amplitude of a late ERP component between 400 and 600 ms. Interestingly, the P3 amplitude of the auditory oddball response was not correlated with accuracy. Conclusions Event-related potentials recorded during a standard auditory oddball session moderately predict aptitude in an audiory and highly in a visual P300 BCI. The predictor will allow for faster paradigm selection. Significance Our method will reduce strain on patients because unsuccessful training may be avoided, provided the results can be generalized to the patient population. KW - experimental design KW - acoustic signals KW - amyotrophic lateral sclerosis KW - man-computer interface KW - electroencephalography KW - event-related potentials KW - physical properties KW - vision Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130327 VL - 8 IS - 2 ER - TY - JOUR A1 - Kübler, Andrea A1 - Hautzinger, Martin A1 - Ludolph, Albert A1 - Dickhaus, Thorsten A1 - Real, Ruben G. L. T1 - Well-being in amyotrophic lateral sclerosis: a pilot experience sampling study N2 - Objective: The aim of this longitudinal study was to identify predictors of instantaneous well-being in patients with amyotrophic lateral sclerosis (ALS). Based on flow theory well-being was expected to be highest when perceived demands and perceived control were in balance, and that thinking about the past would be a risk factor for rumination which would in turn reduce well-being. Methods: Using the experience sampling method, data on current activities, associated aspects of perceived demands, control, and well-being were collected from 10 patients with ALS three times a day for two weeks. Results: Results show that perceived control was uniformly and positively associated with well-being, but that demands were only positively associated with well-being when they were perceived as controllable. Mediation analysis confirmed thinking about the past, but not thinking about the future, to be a risk factor for rumination and reduced well-being. Discussion: Findings extend our knowledge of factors contributing to well-being in ALS as not only perceived control but also perceived demands can contribute to well-being. They further show that a focus on present experiences might contribute to increased well-being. KW - amyotrophic lateral sclerosis KW - ALS KW - coping KW - well-being KW - experience sampling KW - ESM KW - reminiscence KW - rumination Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113057 ER - TY - JOUR A1 - Münßinger, Jana I. A1 - Halder, Sebastian A1 - Kleih, Sonja C. A1 - Furdea, Adrian A1 - Raco, Valerio A1 - Hösle, Adi A1 - Kübler, Andrea T1 - Brain Painting: first evaluation of a new brain-computer interface application with ALS-patients and healthy volunteers N2 - Brain–computer interfaces (BCIs) enable paralyzed patients to communicate; however, up to date, no creative expression was possible. The current study investigated the accuracy and user-friendliness of P300-Brain Painting, a new BCI application developed to paint pictures using brain activity only. Two different versions of the P300-Brain Painting application were tested: A colored matrix tested by a group of ALS-patients (n = 3) and healthy participants (n = 10), and a black and white matrix tested by healthy participants (n = 10). The three ALS-patients achieved high accuracies; two of them reaching above 89% accuracy. In healthy subjects, a comparison between the P300-Brain Painting application (colored matrix) and the P300-Spelling application revealed significantly lower accuracy and P300 amplitudes for the P300-Brain Painting application. This drop in accuracy and P300 amplitudes was not found when comparing the P300-Spelling application to an adapted, black and white matrix of the P300-Brain Painting application. By employing a black and white matrix, the accuracy of the P300-Brain Painting application was significantly enhanced and reached the accuracy of the P300-Spelling application. ALS-patients greatly enjoyed P300-Brain Painting and were able to use the application with the same accuracy as healthy subjects. P300-Brain Painting enables paralyzed patients to express themselves creatively and to participate in the prolific society through exhibitions. KW - Psychologie KW - brain–computer interfaces KW - P300 KW - amyotrophic lateral sclerosis KW - event-related potential Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68168 ER -