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Edward Pokrishevsky, Jeremy Nan, Neil R Cashman
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration and loss of motor neurons that appears to spread through the neuroaxis in a spatiotemporally restricted manner. In the familial form of ALS, the presence of any one of over 180 inherited mutations in the gene that encodes Cu/Zn superoxide dismutase (SOD1) leads to its eventual misfolding and aggregation. Once the pathological SOD1 seed is formed, it can continue growing into a larger aggregate through nucleation of other SOD1 substrate molecules...
2019: Methods in Molecular Biology
Alireza Abdolvahabi, Sanaz Rasouli, Corbin M Croom, Devon L Plewman
Investigating in vitro kinetics of superoxide dismutase-1 (SOD1) aggregation with high-throughput microplate-based assays provides valuable information regarding SOD1 pathogenesis in amyotrophic lateral sclerosis (ALS) and opens venues for the development of effective therapies. In this chapter, we first explain the step-by-step purification and demetallation of wild-type (WT) and ALS-variant SOD1 proteins from Saccharomyces cerevisiae (baker's yeast). We then describe the methodology for a microplate-based fluorescence assay that is used to study real-time kinetics of metal-free (apo)-SOD1 aggregation...
2019: Methods in Molecular Biology
Joana S Cristóvão, Bárbara J Henriques, Cláudio M Gomes
Proteins exhibit a remarkable structural plasticity and may undergo conformational changes resulting in protein misfolding both in a biological context and upon perturbing physiopathological conditions. Such nonfunctional protein conformers, including misfolded states and aggregates, are often associated to protein folding diseases. Understanding the biology of protein folding diseases thus requires tools that allow the structural characterization of nonnative conformations of proteins and their interconversions...
2019: Methods in Molecular Biology
Youngjo Kim, Hyung-Jun Kim, Sun Joo Cha, Hyun-Jun Choi, Hayoung Kim, Sanghyun Lee, Yu-Mi Jeon, Mihye Lee, Seongsoo Lee, Kiyoung Kim
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that is characterized pathologically by the loss of motor neurons. Mutations in the TAF15 gene have been implicated in the pathogenesis of ALS. TATA-binding protein associated factor 15 (TAF15) accumulates as cytoplasmic aggregates in neuronal cells, the clearance of which may be a therapeutic strategy for ALS. However, the identification of a novel regulator for protection against a TAF15-induced proteinopathy and the exact pathogenic mechanism of TAF15-induced neurodegeneration remain to be elucidated...
September 22, 2018: Neurobiology of Aging
M Ahangaran, M R Jahed-Motlagh, B Minaei-Bidgoli
One of the most important issues in predictive modeling is to determine major cause factors of a phenomenon and causal relationships between them. Extracting causal relationships between parameters in a natural phenomenon can be accomplished through checking the parameters' changes in consecutive events. In addition, using information and probabilistic theory help better conception of causal relationships of a phenomenon. Therefore, probabilistic causal discovery from sequential data of a natural phenomenon can be useful for dimension reduction and predicting the future trend of a process...
October 16, 2018: Journal of Biomedical Informatics
Sapna Pathak, James B Caress, Marlena Wosiski-Kuhn, Carol Milligan, Delaney Willia, Michael S Cartwright
INTRODUCTION: This study explores the reliability and responsiveness of neuromuscular ultrasound in amyotrophic lateral sclerosis (ALS). METHODS: Investigations were conducted on 10 healthy controls, 10 ALS patients (single point in time), and 10 different ALS patients (followed over six months; 4 completed follow-up). Ultrasound was used to measure the thickness of the geniohyoid, bilateral biceps/brachialis, bilateral tibialis anterior, and bilateral hemidiaphragms (at inspiration and expiration)...
October 19, 2018: Muscle & Nerve
Shenghan Zhou, Yuliang Zhou, Silin Qian, Wenbing Chang, Liping Wang, Dongsheng Fan
OBJECTIVE: To determine the incidence of amyotrophic lateral sclerosis (ALS) in Beijing from 2010 to 2015 and to address the issue of prognosis. METHODS: The number of patients diagnosed with ALS was generated from two aspects, namely, diagnostic hospitals and assisted care institutions. By examining the consistency of the overlapping data in terms of age and gender distributions, the number of ALS patients in Beijing was estimated to analyze the incidence. Finally, a prognosis study was carried out by sorting the clinical data of deceased patients to associate time to death with the demographic characteristics, including gender, age at diagnosis, site of onset, body mass index, and lag from onset to diagnosis...
October 19, 2018: Brain and Behavior
Xin Jiang, Tao Zhang, Haifang Wang, Tao Wang, Meiling Qin, Puhua Bao, Ruiqi Wang, Yuwei Liu, Hung-Chun Chang, Jun Yan, Jin Xu
Background: Circadian rhythms are oscillating physiological and behavioral changes governed by an internal molecular clock, and dysfunctions in circadian rhythms have been associated with ageing and various neurodegenerative diseases. However, the evidence directly connecting the neurodegeneration-associated proteins to circadian control at the molecular level remains sparse. Methods: Using meta-analysis, synchronized animals and cell lines, cells and tissues from FUS R521C knock-in rats, we examined the role of FUS in circadian gene expression regulation...
2018: Translational Neurodegeneration
Martin Gorges, Kelly Del Tredici, Jens Dreyhaupt, Heiko Braak, Albert C Ludolph, Hans-Peter Müller, Jan Kassubek
A sequential transaxonal disease spread of amyotrophic lateral sclerosis (ALS)-associated TDP-43 pathology in four stages has been defined by post-mortem data, which have been transferred to in vivo imaging by diffusion tensor imaging (DTI) studies. Here, we aimed to investigate whether DTI meta-data are consistent with this proposed pattern of progression in ALS. A systematic literature search using the search engines PubMed and Scopus yielded a total of 370 publications. Of these, 57 studies with cross-sectional data and 10 longitudinal studies of human whole-brain analyses of fractional anisotropy (FA) were included in the final data analysis...
October 18, 2018: Scientific Reports
Yuan Jiang, Long Yan, Longkuo Xia, Xiaoyin Lu, Wenliang Zhu, Dewen Ding, Mingxia Du, Da Zhang, Hongmei Wang, Baoyang Hu
Human pluripotent stem cells hold great promise for improving regenerative medicine. However, a risk for tumor formation and difficulties in generating large amounts of subtype derivatives remain the major obstacles for clinical applications of stem cells. Here, we discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is highly expressed upon differentiation of human embryonic stem cells (hESCs) into neuronal precursors. CRISPR/Cas9-mediated ZEB1 depletion did not impede neural fate commitment, but  prevented hESCs-derived neural precursors from differentiating into neurons, indicating that ZEB1 is required for neuronal differentiation...
October 18, 2018: Journal of Biological Chemistry
Xiangyi Liu, Chujun Wu, Ji He, Nan Zhang, Dongsheng Fan
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. A recent study has identified mutations in the ANXA11 gene (encoding the calcium-binding protein annexin A11) associated with ALS. Mutation screening of ANXA11 protein-coding exons was performed in a Chinese cohort of 434 patients with sporadic ALS and 50 index patients with familial ALS. Polymerase chain reaction and Sanger sequencing were used for mutation detection. We failed to discover an N-terminal mutation, which was common in the Caucasian cohort...
September 22, 2018: Neurobiology of Aging
Clémence Fournier, Mathieu Barbier, Agnès Camuzat, Vincent Anquetil, Serena Lattante, Fabienne Clot, Cécile Cazeneuve, Daisy Rinaldi, Philippe Couratier, Vincent Deramecourt, Mario Sabatelli, Serge Belliard, Martine Vercelletto, Sylvie Forlani, Ludmila Jornea, Eric Leguern, Alexis Brice, Isabelle Le Ber
A (GGGGCC)n repeat expansion in C9orf72 gene is the major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The relations between the repeats size and the age at disease onset (AO) or the clinical phenotype (FTD vs. ALS) were investigated in 125 FTD, ALS, and presymptomatic carriers. Positive correlations were found between repeats number and the AO (p < 10e-4 ) but our results suggested that the association was mainly driven by age at collection (p < 10e-4 ). A weaker association was observed with clinical presentation (p = 0...
September 19, 2018: Neurobiology of Aging
Wilson Barnabas
Brain specific drug delivery is one of the most interesting and challenging areas of research. The blood-brain barrier separates the brain from blood and acts as a barrier to protect the brain from microorganisms, neurotoxins and chemical substances. But, the same mechanism poses an obstacle for the entry of many drugs into the brain. Worldwide, approximately 1.5 billion people are suffering from CNS disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, HIV-dementia and others...
October 15, 2018: Journal of Neuroscience Methods
Bernd L Fiebich, Carla Ribeiro Alvares Batista, Soraya Wilke Saliba, Nizar M Yousif, Antonio Carlos Pinheiro de Oliveira
Toll-like receptors (TLRs) are a group of receptors widely distributed in the organism. In the central nervous system, they are expressed in neurons, astrocytes and microglia. Although their involvement in immunity is notorious, different articles have demonstrated their roles in physiological and pathological conditions, including neurodegeneration. There is increasing evidence of an involvement of TLRs, especially TLR2, 4 and 9 in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)...
2018: Frontiers in Cellular Neuroscience
Lisa M Sharkey, Nathaniel Safren, Amit S Pithadia, Julia E Gerson, Mark Dulchavsky, Svetlana Fischer, Ronak Patel, Gabrielle Lantis, Naila Ashraf, John H Kim, Alia Meliki, Eiko N Minakawa, Sami J Barmada, Magdalena I Ivanova, Henry L Paulson
UBQLN2 is one of a family of proteins implicated in ubiquitin-dependent protein quality control and integrally tied to human neurodegenerative disease. Whereas wild-type UBQLN2 accumulates in intraneuronal deposits in several common age-related neurodegenerative diseases, mutations in the gene encoding this protein result in X-linked amyotrophic lateral sclerosis/frontotemporal dementia associated with TDP43 accumulation. Using in vitro protein analysis, longitudinal fluorescence imaging and cellular, neuronal, and transgenic mouse models, we establish that UBQLN2 is intrinsically prone to self-assemble into higher-order complexes, including liquid-like droplets and amyloid aggregates...
October 17, 2018: Proceedings of the National Academy of Sciences of the United States of America
Rocio Garcia-Santibanez, Matthew Burford, Robert C Bucelli
PURPOSE OF REVIEW: This article provides an overview of recent advancements in the fields of hereditary motor neuropathies and ALS. RECENT FINDINGS: There has been a robust growth in our knowledge and understanding of hereditary and degenerative motor neuronopathies/neuropathies over the last decade. Many breakthroughs in the field of hereditary motor neuropathies (HMN) have been associated with identification and characterization of the genes and molecular mechanisms underlying these disorders...
October 17, 2018: Current Neurology and Neuroscience Reports
Yuewei Sheng, Joseph Capri, Alan Waring, Joan Selverstone Valentine, Julian Whitelegge
Solvent-accessibility change plays a critical role in protein misfolding and aggregation, the culprit for several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mass spectrometry-based hydroxyl radical (·OH) protein footprinting has evolved as a powerful and fast tool in elucidating protein solvent accessibility. In this work, we used fast photochemical oxidation of protein (FPOP) hydroxyl radical (·OH) footprinting to investigate solvent accessibility in human copper-zinc superoxide dismutase (SOD1), misfolded or aggregated forms of which underlie a portion of ALS cases...
October 16, 2018: Journal of the American Society for Mass Spectrometry
Sander Beel, Sarah Herdewyn, Raheem Fazal, Mathias De Decker, Matthieu Moisse, Wim Robberecht, Ludo Van Den Bosch, Philip Van Damme
BACKGROUND: TAR DNA binding protein 43 (TDP-43) is the main disease protein in most patients with amyotrophic lateral sclerosis (ALS) and about 50% of patients with frontotemporal dementia (FTD). TDP-43 pathology is not restricted to patients with missense mutations in TARDBP, the gene encoding TDP-43, but also occurs in ALS/FTD patients without known genetic cause or in patients with various other ALS/FTD gene mutations. Mutations in progranulin (GRN), which result in a reduction of ~ 50% of progranulin protein (PGRN) levels, cause FTD with TDP-43 pathology...
October 16, 2018: Molecular Neurodegeneration
Joshua Petimar, Éilis O'Reilly, Hans-Olov Adami, Piet A van den Brandt, Julie Buring, Dallas R English, D Michal Freedman, Graham G Giles, Niclas Håkansson, Tobias Kurth, Susanna C Larsson, Kim Robien, Leo J Schouten, Elisabete Weiderpass, Alicja Wolk, Stephanie A Smith-Warner
BACKGROUND: Caffeine is associated with a lower risk of some neurological diseases, but few prospective studies have investigated caffeine intake and risk of amyotrophic lateral sclerosis (ALS) mortality. We therefore determined associations between coffee, tea, and caffeine intake and risk of ALS mortality. METHODS: We conducted pooled analyses of eight international, prospective cohort studies, including 351,565 individuals (120,688 men and 230,877 women). We assessed coffee, tea, and caffeine intake using validated food frequency questionnaires administered at baseline...
October 16, 2018: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
Tatsuya Osaki, Sebastien G M Uzel, Roger D Kamm
Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease involving loss of motor neurons (MNs) and muscle atrophy, still has no effective treatment, despite much research effort. To provide a platform for testing drug candidates and investigating the pathogenesis of ALS, we developed an ALS-on-a-chip technology (i.e., an ALS motor unit) using three-dimensional skeletal muscle bundles along with induced pluripotent stem cell (iPSC)-derived and light-sensitive channelrhodopsin-2-induced MN spheroids from a patient with sporadic ALS...
October 2018: Science Advances
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