scholarly journals Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

2019 ◽  
Author(s):  
Oliver H. Tam ◽  
Nikolay V. Rozhkov ◽  
Regina Shaw ◽  
Duyang Kim ◽  
Isabel Hubbard ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Subtypes ◽  
Machine Learning Algorithms ◽  
Tissue Samples ◽  
Proteotoxic Stress ◽  
Sporadic Als ◽  
History Of ◽  
Als Patients ◽  
Large Survey ◽  
Lateral Sclerosis

SummaryAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several inherited pathogenic mutations have been identified as causative, the vast majority of cases are sporadic with no family history of disease. Thus, for the majority of ALS cases, a specific causal abnormality is not known and the disease may be a product of multiple inter-related pathways contributing to varying degrees in different ALS patients. Using unsupervised machine learning algorithms, we stratified the transcriptomes of 148 ALS decedent cortex tissue samples into three distinct and robust molecular subtypes. The largest cluster, identified in 61% of patient samples, displayed hallmarks of oxidative and proteotoxic stress. Another 20% of the ALS patient samples exhibited high levels of retrotransposon expression and other signatures of TDP-43 dysfunction. Finally, a third group showed predominant signatures of glial activation (19%). Together these results demonstrate that at least three distinct molecular signatures contribute to ALS disease. While multiple dysregulated components and pathways comprising these clusters have previously been implicated in ALS pathogenesis, unbiased analysis of this large survey demonstrated that sporadic ALS patient tissues can be segregated into distinct molecular subsets.

scholarly journals A Study of Gene Expression Changes in Human Spinal and Oculomotor Neurons; Identifying Potential Links to Sporadic ALS

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 448
Author(s):  
Aayan N. Patel ◽  
Dennis Mathew
Keyword(s):  
Gene Expression ◽  
Disease Progression ◽  
Motor Neurons ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Tissue Samples ◽  
Disease Symptoms ◽  
Sporadic Als ◽  
Oculomotor Neurons ◽  
Als Patients

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes compromised function of motor neurons and neuronal death. However, oculomotor neurons are largely spared from disease symptoms. The underlying causes for sporadic ALS as well as for the resistance of oculomotor neurons to disease symptoms remain poorly understood. In this bioinformatic-analysis, we compared the gene expression profiles of spinal and oculomotor tissue samples from control individuals and sporadic ALS patients. We show that the genes GAD2 and GABRE (involved in GABA signaling), and CALB1 (involved in intracellular Ca2+ ion buffering) are downregulated in the spinal tissues of ALS patients, but their endogenous levels are higher in oculomotor tissues relative to the spinal tissues. Our results suggest that the downregulation of these genes and processes in spinal tissues are related to sporadic ALS disease progression and their upregulation in oculomotor neurons confer upon them resistance to ALS symptoms. These results build upon prevailing models of excitotoxicity that are relevant to sporadic ALS disease progression and point out unique opportunities for better understanding the progression of neurodegenerative properties associated with sporadic ALS.

scholarly journals Glial Cells in Amyotrophic Lateral Sclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Jurate Lasiene ◽  
Koji Yamanaka
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Glial Cells ◽  
Motor Neurons ◽  
Premature Death ◽  
Active Role ◽  
Sporadic Als ◽  
Neuron Damage ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult motor neuron disease characterized by premature death of upper and lower motor neurons. Two percent of ALS cases are caused by the dominant mutations in the gene for superoxide dismutase 1 (SOD1) through a gain of toxic property of mutant protein. Genetic and chimeric mice studies using SOD1 models indicate that non-neuronal cells play important roles in neurodegeneration through non-cell autonomous mechanism. We review the contribution of each glial cell type in ALS pathology from studies of the rodent models and ALS patients. Astrogliosis and microgliosis are not only considerable hallmarks of the disease, but the intensity of microglial activation is correlated with severity of motor neuron damage in human ALS. The impaired astrocytic functions such as clearance of extracellular glutamate and release of neurotrophic factors are implicated in disease. Further, the damage within astrocytes and microglia is involved in accelerated disease progression. Finally, other glial cells such as NG2 cells, oligodendrocytes and Schwann cells are under the investigation to determine their contribution in ALS. Accumulating knowledge of active role of glial cells in the disease should be carefully applied to understanding of the sporadic ALS and development of therapy targeted for glial cells.

scholarly journals MicroRNAs as Biomarkers in Amyotrophic Lateral Sclerosis

Cells ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 219 ◽  
Author(s):  
Claudia Ricci ◽  
Carlotta Marzocchi ◽  
Stefania Battistini
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Neurological Diseases ◽  
High Specificity ◽  
Practical Applications ◽  
Advantages And Disadvantages ◽  
Specificity And Sensitivity ◽  
Sporadic Als ◽  
History Of ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal disorder characterized by the progressive loss of motor neurons in the cerebral cortex, brain stem, and spinal cord. Sporadic ALS form accounts for the majority of patients, but in 1–13.5% of cases the disease is inherited. The diagnosis of ALS is mainly based on clinical assessment and electrophysiological examinations with a history of symptom progression and is then made with a significant delay from symptom onset. Thus, the identification of biomarkers specific for ALS could be of a fundamental importance in the clinical practice. An ideal biomarker should display high specificity and sensitivity for discriminating ALS from control subjects and from ALS-mimics and other neurological diseases, and should then monitor disease progression within individual patients. microRNAs (miRNAs) are considered promising biomarkers for neurodegenerative diseases, since they are remarkably stable in human body fluids and can reflect physiological and pathological processes relevant for ALS. Here, we review the state of the art of miRNA biomarker identification for ALS in cerebrospinal fluid (CSF), blood and muscle tissue; we discuss advantages and disadvantages of different approaches, and underline the limits but also the great potential of this research for future practical applications.

scholarly journals ALS Motor Neurons Exhibit Hallmark Metabolic Defects That Are Rescued by Nicotinamide and SIRT3 Activation

2019 ◽  
Author(s):  
Jin-Hui Hor ◽  
Munirah Mohamad Santosa ◽  
Valerie Jing Wen Lim ◽  
Beatrice Xuan Ho ◽  
Amy Taylor ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Cortical Neurons ◽  
Metabolic Flux ◽  
Metabolic Profiles ◽  
Metabolic Defects ◽  
Sporadic Als ◽  
Altered Metabolism ◽  
Induced Pluripotent ◽  
Als Patients ◽  
Lateral Sclerosis

SUMMARYMotor neurons (MNs) are highly energetic cells and recent studies suggest that altered energy metabolism precede MN loss in Amyotrophic Lateral Sclerosis (ALS), an age-onset neurodegenerative disease. However, clear mechanistic insights linking altered metabolism and MN death are still missing. In this study, induced pluripotent stem cells (iPSCs) from healthy controls, familial ALS and sporadic ALS patients were differentiated towards spinal MNs, cortical neurons and cardiomyocytes. Metabolic flux analyses reveal a MN-specific deficiency in mitochondrial respiration in ALS. Intriguingly, all forms of familial and sporadic ALS MNs tested in our study exhibited similar defective metabolic profiles, which were attributed to hyper-acetylation of mitochondrial proteins. In the mitochondria, SIRT3 functions as a mitochondrial deacetylase to maintain mitochondrial function and integrity. We found that activating SIRT3 using nicotinamide or a small molecule activator reversed the defective metabolic profiles in all our ALS MNs, as well as correct a constellation of ALS-associated phenotypes.

scholarly journals A Novel Variant in Superoxide Dismutase 1 Gene (p.V119M) in Als Patients with Pure Lower Motor Neuron Presentation

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1544
Author(s):  
Claudia Ricci ◽  
Fabio Giannini ◽  
Giulia Riolo ◽  
Silvia Bocci ◽  
Stefania Casali ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Lower Limbs ◽  
Lower Motor Neuron ◽  
Superoxide Dismutase 1 ◽  
Sporadic Als ◽  
Novel Variant ◽  
History Of ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disorder characterized by degeneration of motor neurons in the cerebral cortex, brain stem, and spinal cord. Most cases of ALS appear sporadically, but 5–10% of patients have a family history of disease. Mutations in the superoxide dismutase 1 gene (SOD1) have been found in 12–23% of familial cases and in 1–2% of sporadic cases. Currently, more than 180 different SOD1 gene variants have been identified in ALS patients. Here, we describe two apparently sporadic ALS patients carrying the same SOD1 c.355G>A variant, leading to the p.V119M substitution, not previously described. Both the patients showed pure lower motor neuron phenotype. The former presented with the flail leg syndrome, a rare ALS variant, characterized by progressive distal onset weakness and atrophy of lower limbs, slow progression and better survival than typical ALS. The latter exhibited rapidly progressive weakness of upper and lower limbs, neither upper motor neuron nor bulbar involvement, and shorter survival than typical ALS. We provide an accurate description of the phenotype, and a bioinformatics analysis of the p.V119M variant on protein structure. This study may increase the knowledge about genotype-phenotype correlations in ALS and improve the approach to ALS patients.

scholarly journals ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation

2020 ◽  
Author(s):  
Jin-Hui Hor ◽  
Munirah Mohamad Santosa ◽  
Valerie Jing Wen Lim ◽  
Beatrice Xuan Ho ◽  
Amy Taylor ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Cortical Neurons ◽  
Metabolic Flux ◽  
Metabolic Profiles ◽  
Metabolic Defects ◽  
Sporadic Als ◽  
Altered Metabolism ◽  
Induced Pluripotent ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Motor neurons (MNs) are highly energetic cells and recent studies suggest that altered energy metabolism precede MN loss in amyotrophic lateral sclerosis (ALS), an age-onset neurodegenerative disease. However, clear mechanistic insights linking altered metabolism and MN death are still missing. In this study, induced pluripotent stem cells from healthy controls, familial ALS, and sporadic ALS patients were differentiated toward spinal MNs, cortical neurons, and cardiomyocytes. Metabolic flux analyses reveal an MN-specific deficiency in mitochondrial respiration in ALS. Intriguingly, all forms of familial and sporadic ALS MNs tested in our study exhibited similar defective metabolic profiles, which were attributed to hyper-acetylation of mitochondrial proteins. In the mitochondria, Sirtuin-3 (SIRT3) functions as a mitochondrial deacetylase to maintain mitochondrial function and integrity. We found that activating SIRT3 using nicotinamide or a small molecule activator reversed the defective metabolic profiles in all our ALS MNs, as well as correct a constellation of ALS-associated phenotypes.

scholarly journals A novel mutation in the RRM2 domain of TDP-43 in a Brazilian sporadic ALS patient.

2021 ◽  
Author(s):  
Amanda Cambraia ◽  
Mario Campos Junior ◽  
Fernanda Gubert ◽  
Juliana Ferreira Vasques ◽  
Marli Pernes da Silva Loureiro ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Rio De Janeiro ◽  
Novel Mutation ◽  
In Silico Analysis ◽  
Sporadic Als ◽  
Sporadic Cases ◽  
Next Generation Sequencing Ngs ◽  
Als Patients ◽  
Silico Analysis ◽  
Lateral Sclerosis

Introduction: Amyotrophic Lateral Sclerosis (ALS) is an adult-onset progressive and fatal neurodegenerative disease that selectively affects upper and lower motor neurons. Death occurs within 3 to 5 years of onset, usually from respiratory complications. Most cases of ALS are sporadic (SALS), but familial forms of the disease (FALS) represent approximately 10% of the cases. More than 30 genes have been associated with ALS and mutations in these genes account for more than a half of all familial cases and about 10% of sporadic cases. One of the most prevalent genes is TARDBP, responsible for approximately 4-6% of FALS and nearly 1-2% of SALS cases. The aim of this study was to perform the screening of known ALS genes, to increase the knowledge of the mutations that circulate in the population from Rio de Janeiro. Methods: The screening of mutations was performed through the Illumina Next Generation Sequencing (NGS) platform with the use of a sequencing panel that contained the TARDBP, SOD1, FUS, VAPB, SMN1 and SMN2 genes. Results: A novel missense mutation (p.Phe194Leu) in exon 5 of the TARDBP gene was found in a sporadic male patient who died at the age of 58 (2018). The mutation, a TTT/CTT substitution, was not detected in any mutation databases and in the literature. In silico analysis of this variant with different algorithms were performed and the results pointed to a probably damaging impact and that the mutation is disease causing. Conclusion: Through the study of the ALS genes by the NGS, we were able to identify a novel TARDBP mutation in a non-familial ALS patient. In addition, this study also increases the number of known TARDBP mutations in ALS patients and our knowledge of the mutations that affect the patients from of population from Rio de Janeiro.

TDP–43, Protein Aggregation, and Amyotrophic Lateral Sclerosis

US Neurology ◽  
2010 ◽  
Vol 05 (02) ◽  
pp. 35 ◽  
Author(s):  
Edor Kabashi ◽  
Paul N Valdmanis ◽  
Hussein Daoud ◽  
Véronique V Belzil ◽  
Patrick A Dion ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Inclusion Bodies ◽  
Missense Mutations ◽  
Cellular Models ◽  
Truncating Mutation ◽  
C Terminus ◽  
History Of ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder and the third most common neurodegenerative cause of adult death after Alzheimer’s and Parkinson’s diseases. TAR DNA binding protein (TDP-43) has been found to be a major component of inclusion bodies in motor neurons of ALS patients. Inclusion bodies are protein aggregates considered a pathological hallmark of neurodegeneration. Our group and eight independent research groups screened TDP-43 for mutations. Overall, 19 missense mutations and one truncating mutation were identified only in ALS patients. These mutations were not found in a considerable number of controls sequenced in several independent studies. Ten of these mutations were found in patients with a family history of ALS. To further support a pathogenic role, the mutations segregated with the disease in three families, including one family with a significant logarithm of odds (LOD) score. Nineteen of these 20 mutations are located in the C-terminus of the TDP-43 protein. These mutations could disrupt several of the already known functions of TDP-43, including nuclear localization, exon splicing, and RNA and heterogenous ribonucleoprotein particle (hnRNP) binding, or could introduce a novel gain of function that is toxic to motor neurons. In the future, animal and cellular models using these mutations should elucidate the role of TDP-43 mutations in ALS pathogenesis and could provide new means to test pharmaceutical compounds for this neurological disease.

Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 17 (3) ◽  
pp. 275-285 ◽  
Author(s):  
Si Chen ◽  
Qiao Liao ◽  
Ke Lu ◽  
Jinxia Zhou ◽  
Cao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Rat Model ◽  
Microglial Activation ◽  
Transgenic Rat ◽  
Intragastric Administration ◽  
Behavioral Deficits ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Transgenic Rat Model

Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.

scholarly journals Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James C. Dodge ◽  
Jinlong Yu ◽  
S. Pablo Sardi ◽  
Lamya S. Shihabuddin
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Cholesterol Homeostasis ◽  
Cholesterol Oxidation ◽  
Therapeutic Approaches ◽  
Cellular Survival ◽  
Sporadic Als ◽  
Human Motor ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.

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