@article{MarkertSkoruppaYuetal.2020, author = {Markert, Sebastian M. and Skoruppa, Michael and Yu, Bin and Mulcahy, Ben and Zhen, Mai and Gao, Shangbang and Sendtner, Michael and Stigloher, Christian}, title = {Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission}, series = {Biology Open}, volume = {9}, journal = {Biology Open}, doi = {10.1242/bio.055129}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230662}, year = {2020}, abstract = {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.}, language = {en} } @article{BrieseSaalBauernschubertLueningschroeretal.2020, author = {Briese, Michael and Saal-Bauernschubert, Lena and L{\"u}ningschr{\"o}r, Patrick and Moradi, Mehri and Dombert, Benjamin and Surrey, Verena and Appenzeller, Silke and Deng, Chunchu and Jablonka, Sibylle and Sendtner, Michael}, title = {Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function}, series = {Acta Neuropathologica Communications}, volume = {8}, journal = {Acta Neuropathologica Communications}, doi = {10.1186/s40478-020-00987-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230322}, year = {2020}, abstract = {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.}, language = {en} } @article{ErlbeckMochtyKuebleretal.2017, author = {Erlbeck, Helena and Mochty, Ursula and K{\"u}bler, Andrea and Real, Ruben G. L.}, title = {Circadian course of the P300 ERP in patients with amyotrophic lateral sclerosis - implications for brain-computer interfaces (BCI)}, series = {BMC Neurology}, volume = {17}, journal = {BMC Neurology}, number = {3}, doi = {10.1186/s12883-016-0782-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157423}, year = {2017}, abstract = {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.}, language = {en} } @phdthesis{Saal2017, author = {Saal, Lena}, title = {Whole transcriptome profiling of compartmentalized motoneurons}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140006}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Spinal muscular atrophy and amyotrophic lateral sclerosis are the two most common devastating motoneuron diseases. The mechanisms leading to motoneuron degeneration are not resolved so far, although different hypotheses have been built on existing data. One possible mechanism is disturbed axonal transport of RNAs in the affected motoneurons. The underlying question of this study was therefore to characterize changes in transcript levels of distinct RNAs in cell culture models of spinal muscular atrophy and amyotrophic lateral sclerosis, especially in the axonal compartment of primary motoneurons. To investigate this in detail we first established compartmentalized cultures of Primary mouse motoneurons. Subsequently, total RNA of both compartments was extracted separately and either linearly amplified and subjected to microarray profiling or whole transcriptome amplification followed by RNA-Sequencing was performed. To make the whole transcriptome amplification method suitable for compartmentalized cultures, we adapted a double-random priming strategy. First, we applied this method for initial optimization onto serial dilutions of spinal cord RNA and later on to the compartmentalized motoneurons. Analysis of the data obtained from wildtype cultures already revealed interesting results. First, the RNA composition of axons turned out to be highly similar to the somatodendritic compartment. Second, axons seem to be particularly enriched for transcripts related to protein synthesis and energy production. In a next step we repeated the experiments by using knockdown cultures. The proteins depleted hereby are Smn, Tdp-43 and hnRNP R. Another experiment was performed by knocking down the non-coding RNA 7SK, the main interacting RNA of hnRNP R. Depletion of Smn led to a vast number of deregulated transcripts in the axonal and somatodendritic compartment. Transcripts downregulated in the axons upon Smn depletion were especially enriched for GOterms related to RNA processing and encode proteins located in neuron projections including axons and growth cones. Strinkingly, among the upregulated transcripts in the somatodendritic compartment we mainly found MHC class I transcripts suggesting a potential neuroprotective role. In contrast, although knockdown of Tdp-43 also revealed a large number of downregulated transcripts in the axonal compartment, these transcripts were mainly associated with functions in transcriptional regulation and RNA splicing. For the hnRNP R knockdown our results were again different. Here, we observed downregulated transcripts in the axonal compartment mainly associated with regulation of synaptic transmission and nerve impulses. Interestingly, a comparison between deregulated transcripts in the axonal compartment of both hnRNP R and 7SK knockdown presented a significant overlap of several transcripts suggesting some common mechanism for both knockdowns. Thus, our data indicate that a loss of disease-associated proteins involved in axonal RNA transport causes distinct transcriptome alterations in motor axons.}, subject = {Axon}, language = {en} } @article{MajounieRentonMoketal.2012, author = {Majounie, Elisa and Renton, Alan E. and Mok, Kin and Dopper, Elise G. P. and Waite, Adrian and Rollinson, Sara and Chi{\`o}, Adriano and Restagno, Gabriella and Nicolaou, Nayia and Simon-Sanchez, Javier and van Swieten, John C. and Abramzon, Yevgeniya and Johnson, Janel O. and Sendtner, Michael and Pamphlett, Roger and Orrell, Richard W. and Mead, Simon and Sidle, Katie C. and Houlden, Henry and Rohrer, Jonathan D. and Morrison, Karen E. and Pall, Hardev and Talbot, Kevin and Ansorge, Olaf and Hernandez, Dena G. and Arepalli, Sampath and Sabatelli, Mario and Mora, Gabriele and Corbo, Massimo and Giannini, Fabio and Calvo, Andrea and Englund, Elisabet and Borghero, Giuseppe and Floris, Gian Luca and Remes, Anne M. and Laaksovirta, Hannu and McCluskey, Leo and Trojanowski, John Q. and Van Deerlin, Vivianna M. and Schellenberg, Gerard D. and Nalls, Michael A. and Drory, Vivian E. and Lu, Chin-Song and Yeh, Tu-Hsueh and Ishiura, Hiroyuki and Takahashi, Yuji and Tsuji, Shoji and Le Ber, Isabelle and Brice, Alexis and Drepper, Carsten and Williams, Nigel and Kirby, Janine and Shaw, Pamela and Hardy, John and Tienari, Pentti J. and Heutink, Peter and Morris, Huw R. and Pickering-Brown, Stuart and Traynor, Bryan J.}, title = {Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study}, series = {The Lancet Neurology}, volume = {11}, journal = {The Lancet Neurology}, doi = {10.1016/S1474-4422(12)70043-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154644}, pages = {323 -- 330}, year = {2012}, abstract = {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.}, language = {en} } @article{HalderHammerKleihetal.2013, author = {Halder, Sebastian and Hammer, Eva Maria and Kleih, Sonja Claudia and Bogdan, Martin and Rosenstiel, Wolfgang and Birbaumer, Niels and K{\"u}bler, Andrea}, title = {Prediction of Auditory and Visual P300 Brain-Computer Interface Aptitude}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130327}, pages = {e53513}, year = {2013}, abstract = {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.}, language = {en} } @article{KueblerHautzingerLudolphetal.2014, author = {K{\"u}bler, Andrea and Hautzinger, Martin and Ludolph, Albert and Dickhaus, Thorsten and Real, Ruben G. L.}, title = {Well-being in amyotrophic lateral sclerosis: a pilot experience sampling study}, doi = {10.3389/fpsyg.2014.00704}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113057}, year = {2014}, abstract = {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.}, language = {en} } @article{MuenssingerHalderKleihetal.2010, author = {M{\"u}nßinger, Jana I. and Halder, Sebastian and Kleih, Sonja C. and Furdea, Adrian and Raco, Valerio and H{\"o}sle, Adi and K{\"u}bler, Andrea}, title = {Brain Painting: first evaluation of a new brain-computer interface application with ALS-patients and healthy volunteers}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68168}, year = {2010}, abstract = {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.}, subject = {Psychologie}, language = {en} }