29,287 results match your criteria Amyotrophic Lateral Sclerosis

UBQLN2-HSP70 axis reduces poly-Gly-Ala aggregates and alleviates behavioral defects in the C9ORF72 animal model.

Neuron 2021 May 6. Epub 2021 May 6.

Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China; Department of Neurobiology, Key Laboratory of Medical Neurobiology of Zhejiang Province, School of Medicine, Zhejiang University, Zhejiang 310020, China. Electronic address:

Expansion of a hexanucleotide repeat GGGGCC (G4C2) in the intron of the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Transcripts carrying G4C2 repeat expansions generate neurotoxic dipeptide repeat (DPR) proteins, including poly-Gly-Ala (poly-GA), which tends to form protein aggregates. Here, we demonstrate that UBQLN2, another ALS/FTD risk factor, is recruited to reduce poly-GA aggregates and alleviate poly-GA-induced neurotoxicity. Read More

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A physiologically-based pharmacokinetic model to describe antisense oligonucleotide distribution after intrathecal administration.

J Pharmacokinet Pharmacodyn 2021 May 15. Epub 2021 May 15.

Clinical Pharmacology and Pharmacometrics, Biogen Inc., 225 Binney Street, Cambridge, MA, 02142, USA.

Antisense oligonucleotides (ASOs) are promising therapeutic agents for a variety of neurodegenerative and neuromuscular disorders, e.g., Alzheimer's, Parkinson's and Huntington's diseases, spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), caused by genetic abnormalities or increased protein accumulation. Read More

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Connecting the "dots": RNP granule network in health and disease.

Biochim Biophys Acta Mol Cell Res 2021 May 11:119058. Epub 2021 May 11.

Medicines Discovery Institute, Cardiff University, Cardiff, CF10 3AT, United Kingdom. Electronic address:

All cells contain ribonucleoprotein (RNP) granules - large membraneless structures composed of RNA and proteins. Recent breakthroughs in RNP granule research have brought a new appreciation of their crucial role in organising virtually all cellular processes. Cells widely exploit the flexible, dynamic nature of RNP granules to adapt to a variety of functional states and the ever-changing environment. Read More

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Drug Repurposing: A Network-based Approach to Amyotrophic Lateral Sclerosis.

Neurotherapeutics 2021 May 13. Epub 2021 May 13.

Institute for Systems Analysis and Computer Science "A. Ruberti", National Research Council (IASI-CNR), Via Dei Taurini 19, 00185, Rome, Italy.

The continuous adherence to the conventional "one target, one drug" paradigm has failed so far to provide effective therapeutic solutions for heterogeneous and multifactorial diseases as amyotrophic lateral sclerosis (ALS), a rare progressive and chronic, debilitating neurological disease for which no cure is available. The present study is aimed at finding innovative solutions and paradigms for therapy in ALS pathogenesis, by exploiting new insights from Network Medicine and drug repurposing strategies. To identify new drug-ALS disease associations, we exploited SAveRUNNER, a recently developed network-based algorithm for drug repurposing, which quantifies the proximity of disease-associated genes to drug targets in the human interactome. Read More

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Possible Somatic Mosaicism of Novel Variant in Familial Amyotrophic Lateral Sclerosis.

Neurol Genet 2021 Feb 12;7(1):e552. Epub 2021 Jan 12.

Department of Neurology (S.H., S. Suzuki, A.M., S. Shimohama), School of Medicine, Sapporo Medical University, Japan; Department of Neurology (A.N., M.A.), Tohoku University School of Medicine, Sendai, Japan; Department of Neurology (E.T.), Sapporo Shirakabadai Hospital, Japan; Department of Medical Genetics and Genomics (A.I., A.S.), School of Medicine, Sapporo Medical University, Japan; Tohoku Medical Megabank Organization (I.N.M.), Tohoku University Graduate School of Information Sciences, Sendai, Japan; and Department of Medical Genetics (Y.A.), Tohoku University School of Medicine, Sendai, Japan.

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February 2021

Unbiased Label-Free Quantitative Proteomics of Cells Expressing Amyotrophic Lateral Sclerosis (ALS) Mutations in Reveals Activation of the Apoptosis Pathway: A Workflow to Screen Pathogenic Gene Mutations.

Front Mol Neurosci 2021 27;14:627740. Epub 2021 Apr 27.

Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia.

The past decade has seen a rapid acceleration in the discovery of new genetic causes of ALS, with more than 20 putative ALS-causing genes now cited. These genes encode proteins that cover a diverse range of molecular functions, including free radical scavenging (e.g. Read More

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Fabricating multifunctional low-toxicity ratiometric fluorescent probe for individual detection of Cu/glutamate and continuous sensing for glutamate via Cu-based platform.

Spectrochim Acta A Mol Biomol Spectrosc 2021 May 1;259:119892. Epub 2021 May 1.

College of Chemistry, Liaoning University, 66 Chongshan Middle Road, Shenyang, Liaoning 110036, People's Republic of China. Electronic address:

Herein, a multifunctional ratiometric fluorescent (RF) probe Fe-MIL-88NH@RhB was fabricated for individual detection of CuGlu and continuous sensing of Glu based on unique coordination principle by encapsulating RhB into the porous of metal-organic-framework-Fe-MIL-88NH. Designed Fe-MIL-88NH@RhB platform could selectively identify Cu(II)/Glu accompanying a turn-off/turn-on fluorescent behavior with good linearity. Moreover, if the Fe-MIL-88NH@RhB/Cu is treated with Glu continuously, the quenching fluorescence of this platform (after Cu sensing at blue emission) would be further in turn restored. Read More

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Articulatory Correlates of Stress Pattern Disturbances in Talkers With Dysarthria.

J Speech Lang Hear Res 2021 May 13:1-14. Epub 2021 May 13.

Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, Nashville, TN.

Purpose Reduced stress commonly occurs in talkers with Parkinson's disease (PD), whereas excessive and equal stress is frequently associated with dysarthria of talkers with amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). This study sought to identify articulatory impairment patterns that underlie these two impaired stress patterns. We further aimed to determine if talkers with the same stress pattern disturbance but different diseases (ALS and MS) exhibit disease-specific articulatory deficits. Read More

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Validation of The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) in behavioural variant Frontotemporal Dementia and Alzheimer's Disease.

Int J Geriatr Psychiatry 2021 May 13. Epub 2021 May 13.

Human Cognitive Neuroscience -Psychology, School of Philosophy, Psychology and Language Sciences, University of Edinburgh.

The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was developed to assess cognitive and behavioural changes in an anterior frontotemporal syndrome (executive functions, language, fluency and behaviour), common in Amyotrophic Lateral Sclerosis (ALS) and also assesses posterior cerebral dysfunction (memory and visuospatial abilities).

Objectives: To validate the ECAS in behavioural variant Frontotemporal Dementia (bvFTD) without ALS, as compared with Alzheimer's Disease (AD), against comprehensive neuropsychological assessment. Compare its sensitivity to that of the Addenbrooke's Cognitive Examination (ACE-III) and investigate behavioural changes in both types of dementia. Read More

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Inactivation of the CB receptor accelerated the neuropathological deterioration in TDP-43 transgenic mice, a model of amyotrophic lateral sclerosis.

Brain Pathol 2021 May 13:e12972. Epub 2021 May 13.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain.

The activation of the cannabinoid receptor type-2 (CB ) afforded neuroprotection in amyotrophic lateral sclerosis (ALS) models. The objective of this study was to further investigate the relevance of the CB receptor through investigating the consequences of its inactivation. TDP-43(A315T) transgenic mice were crossed with CB receptor knock-out mice to generate double mutants. Read More

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Arachidonic Acid Metabolites in Neurologic Disorders.

CNS Neurol Disord Drug Targets 2021 May 11. Epub 2021 May 11.

Selcuk University Faculty of Medicine Neurology, Turkey.

Background & Objective: Arachidonic acid (ARA) is essential for the fluidity, selective permeability, and flexibility of the cell membrane. It is an important factor for the function of all cells, particularly in the nervous system, immune system, and vascular endothelium. ARA, after docosahexaenoic acid, is the second most common polyunsaturated fatty acid in the phospholipids of the nerve cell membrane. Read More

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Widespread displacement of DNA- and RNA-binding factors underlies toxicity of arginine-rich cell-penetrating peptides.

EMBO J 2021 May 12:e103311. Epub 2021 May 12.

Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

Due to their capability to transport chemicals or proteins into target cells, cell-penetrating peptides (CPPs) are being developed as therapy delivery tools. However, and despite their interesting properties, arginine-rich CPPs often show toxicity for reasons that remain poorly understood. Using a (PR)n dipeptide repeat that has been linked to amyotrophic lateral sclerosis (ALS) as a model of an arginine-rich CPP, we here show that the presence of (PR)n leads to a generalized displacement of RNA- and DNA-binding proteins from chromatin and mRNA. Read More

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Intracerebroventricular delivery of vascular endothelial growth factor in patients with amyotrophic lateral sclerosis, a phase I study.

Brain Commun 2020 29;2(2):fcaa160. Epub 2020 Sep 29.

Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium.

We studied the feasibility, safety, tolerability and pharmacokinetics of intracerebroventricular delivery of recombinant human vascular endothelial growth factor in patients with amyotrophic lateral sclerosis. In this phase I study in patients with amyotrophic lateral sclerosis, the study drug was delivered using an implantable programmable pump connected to a catheter inserted in the frontal horn of the lateral cerebral ventricle. A first cohort received open label vascular endothelial growth factor (0. Read More

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September 2020

Expanding the Spectrum of Movement Disorders Associated With Hexanucleotide Expansions.

Neurol Genet 2021 Apr 12;7(2):e575. Epub 2021 Mar 12.

Department of Neurodegenerative Diseases (C.E.-F., D.H.M., S.J.T.), Department of Clinical and Movement Neurosciences (A.L, F.M., E.M., G.D.L., M.M., K.P.B.), and Department of Neuromuscular Disorders (H.H.), UCL Queen Square Institute of Neurology, United Kingdom; Department of Neurosciences, Biomedicine and Movement Sciences (F.M.), University of Verona, Italy; St George's University of London (D.H.M.), United Kingdom; Department of Systems Medicine (G.D.L.), University of Rome Tor Vergata, Italy; and Pacific Parkinson's Research Centre and Djavad Mowafaghian Centre for Brain Health (M.M.), University of British Columbia, Vancouver, Canada.

Objective: Hexanucleotide repeat expansions (HREs) in are a major cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We aimed to determine the frequency and phenomenology of movement disorders (MD) in carriers of HRE in through a retrospective review of patients' medical records.

Methods: We retrospectively reviewed the clinical records of patients carrying a HRE in the pathogenic range and compared the characteristics of patients with and without MD. Read More

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Comprehensive cell type decomposition of circulating cell-free DNA with CelFiE.

Nat Commun 2021 May 11;12(1):2717. Epub 2021 May 11.

Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.

Circulating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising noninvasive biomarker for cell death. Here, we propose an algorithm, CelFiE, to accurately estimate the relative abundances of cell types and tissues contributing to cfDNA from epigenetic cfDNA sequencing. In contrast to previous work, CelFiE accommodates low coverage data, does not require CpG site curation, and estimates contributions from multiple unknown cell types that are not available in external reference data. Read More

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Switching the proteolytic system from the ubiquitin-proteasome system to autophagy in the spinal cord of an amyotrophic lateral sclerosis mouse model.

Neuroscience 2021 May 8. Epub 2021 May 8.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-Ku, Okayama, 700-8558, Japan. Electronic address:

The degradation of damaged proteins takes place via two major proteolytic pathways: the ubiquitin-proteasome system (UPS) and autophagy. However, since it is unclear how these two proteolytic pathways contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), we investigated the switching mechanism from UPS to autophagy by pharmacologically modifying these pathways by treating the spinal cords of female ALS mouse model bearing G93A human SOD1 (G93A mice) with MG132 or 3-methyladenine (3MA). G93A mice exhibited a progressive increase in the amount of ubiquitin and p62 aggregates, BAG3 expression, and LC3-II/LC3-I ratio in both astroglia and motor neurons. Read More

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Genoppi is an open-source software for robust and standardized integration of proteomic and genetic data.

Nat Commun 2021 May 10;12(1):2580. Epub 2021 May 10.

Stanley Center at Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Combining genetic and cell-type-specific proteomic datasets can generate biological insights and therapeutic hypotheses, but a technical and statistical framework for such analyses is lacking. Here, we present an open-source computational tool called Genoppi (lagelab.org/genoppi) that enables robust, standardized, and intuitive integration of quantitative proteomic results with genetic data. Read More

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Pathomechanisms of ALS8: altered autophagy and defective RNA binding protein (RBP) homeostasis due to the VAPB P56S mutation.

Cell Death Dis 2021 May 10;12(5):466. Epub 2021 May 10.

Institute of Neuropathology, RWTH Aachen University Medical School, Pauwelsstr. 30, 52074, Aachen, Germany.

Mutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet. Read More

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Growing role of S100B protein as a putative therapeutic target for neurological- and nonneurological-disorders.

Neurosci Biobehav Rev 2021 May 7;127:446-458. Epub 2021 May 7.

Department of Translational Medicine and Surgery, Section of General Pathology, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 1-8, 00168 Rome, Italy. Electronic address:

S100B is a calcium-binding protein mainly expressed by astrocytes, but also localized in other definite neural and extra-neural cell types. While its presence in biological fluids is widely recognized as a reliable biomarker of active injury, growing evidence now indicates that high levels of S100B are suggestive of pathogenic processes in different neural, but also extra-neural, disorders. Indeed, modulation of S100B levels correlates with the occurrence of clinical and/or toxic parameters in experimental models of diseases such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, muscular dystrophy, multiple sclerosis, acute neural injury, inflammatory bowel disease, uveal and retinal disorders, obesity, diabetes and cancer, thus directly linking the levels of S100B to pathogenic mechanisms. Read More

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