Amyotrophic Lateral Sclerosis

Motor Neuron ◽

Symptom Onset ◽

Muscle Wasting ◽

Neurodegenerative Disorder ◽

Peak Incidence ◽

Respiratory Involvement ◽

Sporadic Als ◽

Bulbar Dysfunction ◽

Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disorder with both upper and lower motor neuron involvement. It presents with weakness, muscle wasting, spasticity involving the limbs, bulbar dysfunction, and, typically later in the disease, respiratory involvement. Up to 20% of patients may also have a frontotemporal-type dementia. Average duration of survival is 2 to 4 years from symptom onset, and the peak incidence is between the ages of 50 and 75 years. Only 10% of patients have familial forms, and the remainder have sporadic ALS.

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

Scientific Reports ◽

10.1038/s41598-020-80378-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

James C. Dodge ◽

Jinlong Yu ◽

S. Pablo Sardi ◽

Lamya S. Shihabuddin

Keyword(s):

Motor Neuron ◽

Cholesterol Homeostasis ◽

Cholesterol Oxidation ◽

Therapeutic Approaches ◽

Cellular Survival ◽

Sporadic Als ◽

Human Motor ◽

Als Patients ◽

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.

Motor neuron translatome reveals deregulation of SYNGR4 and PLEKHB1 in mutant TDP-43 amyotrophic lateral sclerosis models

Human Molecular Genetics ◽

10.1093/hmg/ddaa140 ◽

2020 ◽

Vol 29 (16) ◽

pp. 2647-2661 ◽

Cited By ~ 1

Author(s):

Rita F Marques ◽

Jan B Engler ◽

Katrin Küchler ◽

Ross A Jones ◽

Thomas Lingner ◽

...

Keyword(s):

Spinal Cord ◽

Motor Neuron ◽

Symptom Onset ◽

Rna Binding ◽

Affinity Purification ◽

Disease Onset ◽

Motor Symptom ◽

Pathological Feature ◽

Abstract Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease with progressive loss of motor neuron (MN) function in the brain and spinal cord. Mutations in TARDBP, encoding the RNA-binding protein TDP-43, are one cause of ALS, and TDP-43 mislocalization in MNs is a key pathological feature of >95% of ALS cases. While numerous studies support altered RNA regulation by TDP-43 as a major cause of disease, specific changes within MNs that trigger disease onset remain unclear. Here, we combined translating ribosome affinity purification (TRAP) with RNA sequencing to identify molecular changes in spinal MNs of TDP-43–driven ALS at motor symptom onset. By comparing the MN translatome of hTDP-43A315T mice to littermate controls and to mice expressing wild type hTDP-43, we identified hundreds of mRNAs that were selectively up- or downregulated in MNs. We validated the deregulated candidates Tex26, Syngr4, and Plekhb1 mRNAs in an independent TRAP experiment. Moreover, by quantitative immunostaining of spinal cord MNs, we found corresponding protein level changes for SYNGR4 and PLEKHB1. We also observed these changes in spinal MNs of an independent ALS mouse model caused by a different patient mutant allele of TDP-43, suggesting that they are general features of TDP-43-driven ALS. Thus, we identified SYNGR4 and PLEKHB1 to be deregulated in MNs at motor symptom onset in TDP-43-driven ALS models. This spatial and temporal pattern suggests that these proteins could be functionally important for driving the transition to the symptomatic phase of the disease.

The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis

Science Translational Medicine ◽

10.1126/scitranslmed.aaf3962 ◽

2017 ◽

Vol 9 (391) ◽

pp. eaaf3962 ◽

Cited By ~ 90

Author(s):

Keiko Imamura ◽

Yuishin Izumi ◽

Akira Watanabe ◽

Kayoko Tsukita ◽

Knut Woltjen ◽

...

Keyword(s):

Motor Neuron ◽

Motor Neurons ◽

New Drugs ◽

Small Interfering Rnas ◽

Altered Expression ◽

Sporadic Als ◽

Induced Pluripotent ◽

Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72. Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.

Incidence and Characteristics of Spinal Decompression Surgery after the Onset of Symptoms of Amyotrophic Lateral Sclerosis

Neurosurgery ◽

10.1227/01.neu.0000180028.64385.d3 ◽

2005 ◽

Vol 57 (5) ◽

pp. 984-989 ◽

Cited By ~ 18

Author(s):

Daniel Yoshor ◽

Arnett Klugh ◽

Stanley H. Appel ◽

Lanny J. Haverkamp

Keyword(s):

Symptom Onset ◽

Spinal Surgery ◽

Foot Drop ◽

Spinal Decompression ◽

Sporadic Als ◽

Number Of Patients ◽

Als Patients ◽

The Impact ◽

Abstract OBJECTIVE: The high incidence of spondylosis in patients at the mean age of onset (55.7 yr) of amyotrophic lateral sclerosis (ALS) can make recognition of ALS as a cause of weakness difficult. METHODS: To assess the impact of this diagnostic dilemma on neurosurgical practice, we performed a retrospective analysis of a database of more than 1500 patients with motor neuron disease. RESULTS: Of 1131 patients with typical, sporadic ALS, 47 (4.2%) underwent decompressive spinal surgery after the onset of retrospectively recognized symptoms of ALS. Among 55 operations in 47 ALS patients, 86% yielded no improvement, 9% produced minor improvement, and only 5% provided significant benefit. Cervical decompression was performed in 56%, lumbar in 42%, and thoracic in 2%. Foot drop was a symptom prompting surgery in 11 patients, and in 10, this finding was subsequently attributed solely to ALS. No differences between ALS patients who underwent spinal decompression and other ALS patients were noted regarding age at symptom onset, severity of impairment at time of diagnosis, or rate of disease progression. Not surprisingly, patients who had spinal surgery tended to have a longer interval between retrospectively recognized symptom onset and diagnosis of ALS. CONCLUSION: A small but significant number of patients with unrecognized ALS undergo spinal surgery that in retrospect may be inappropriate. The possibility of ALS must be considered in the evaluation of patients with weakness even in the presence of radiographic evidence of spondylosis and nerve root or spinal cord impingement.

Amyotrophic Lateral Sclerosis: The Most Common And Lethal Form Of Motor Neuron Disease-a Case Report From Middle East

Journal of Bahria University Medical and Dental College ◽

10.51985/jbumdc2018103 ◽

2019 ◽

Vol 09 (02) ◽

pp. 156-158

Author(s):

Waseem Mehmood Nizamani ◽

Ameet Jesrani ◽

Mujtaba Khan ◽

Kalthoum Tlili ◽

Nader Al Khuraish ◽

...

Keyword(s):

Motor Neuron ◽

Motor Neurons ◽

Clinical Presentation ◽

Neurodegenerative Disorder ◽

Signs And Symptoms ◽

Corticospinal Tracts ◽

Familial Form ◽

Lateral Sclerosis ◽

Made In

A neurodegenerative disorder which is fatal, rapidly progressive and has no effective treatment till date is amyotrophic lateral sclerosis. Almost 90% of all cases occur in the sporadic form, with the rest occurring in the familial form. It is a devastating disease leading to death within 3-5 years in most cases. The diagnosis of AML is difficult to made in spite of acknowledgment for 140 years. It is diagnosed by clinical presentation which is a combination of upper and lower motor neuron signs and electro diagnostic studies which gives information about diffuse motor axonal injury. This neurodegenerative disorder results in degeneration of corticospinal tracts and anterior horn cells and involving motor neurons of the cerebral cortex, brainstem, and spinal cord. There are a variable signs and symptoms of this disease, so the diagnosis is very important for the management and better outcome of the patients. Cause of death in these patients is usually respiratory failure

Neuropathologic description of CHCHD10 mutated amyotrophic lateral sclerosis

Neurology Genetics ◽

10.1212/nxg.0000000000000394 ◽

2020 ◽

Vol 6 (1) ◽

pp. e394

Author(s):

Julia L. Keith ◽

Emily Swinkin ◽

Andrew Gao ◽

Samira Alminawi ◽

Ming Zhang ◽

...

Keyword(s):

Motor Neurons ◽

Mutation Carrier ◽

Double Immunofluorescence ◽

Motor Neuron Degeneration ◽

Respiratory Involvement ◽

Sporadic Als ◽

Immunofluorescence Labeling ◽

Normal Controls ◽

ObjectiveTo present the postmortem neuropathologic report of a patient with a CHCHD10 mutation exhibiting an amyotrophic lateral sclerosis (ALS) clinical phenotype.MethodsA 54-year-old man without significant medical history or family history presented with arm weakness, slowly progressed over 19 years to meet the El Escorial criteria for clinically probable ALS with bulbar and respiratory involvement, and was found to have a CHCHD10 p.R15L mutation. Postmortem neuropathologic examination took place including immunohistochemical staining with CHCHD10, and double immunofluorescence combining CHCHD10 with TDP43 and neurofilament was performed and the results were compared with normal controls and sporadic ALS cases.ResultsPostmortem examination of the CHCHD10 mutation carrier showed severe loss of hypoglossal and anterior horn motor neurons, mild corticospinal tract degeneration, and a relative lack of TDP43 immunopathology. CHCHD10 immunohistochemistry for the 3 controls and the 5 sporadic ALS cases showed strong neuronal cytoplasmic and axonal labeling, with the CHCHD10 mutation carrier also having numerous CHCHD10 aggregates within their anterior horns. These aggregates may be related to the CHCHD10 aggregates recently described to cause mitochondrial degeneration and disease in a tissue-selective toxic gain-of-function fashion in a CHCHD10 knock-in mouse model. The CHCHD10 aggregates did not colocalize with TDP43 and were predominantly extracellular on double immunofluorescence labeling with neurofilament.ConclusionsThe neuropathology of CHCHD10 mutated ALS includes predominantly lower motor neuron degeneration, absent TDP43 immunopathology, and aggregates of predominantly extracellular CHCHD10, which do not contain TDP43.

Glial Cells in Amyotrophic Lateral Sclerosis

Neurology Research International ◽

10.1155/2011/718987 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 62

Author(s):

Jurate Lasiene ◽

Koji Yamanaka

Keyword(s):

Motor Neuron ◽

Glial Cells ◽

Motor Neurons ◽

Premature Death ◽

Active Role ◽

Sporadic Als ◽

Neuron Damage ◽

Als Patients ◽

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.

Progesterone and cortisol levels in sporadic amyotrophic lateral sclerosis (sALS): correlation with prognostic factors

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci.2011.006 ◽

2011 ◽

Vol 6 (1) ◽

Author(s):

Gisella Gargiulo Monachelli ◽

Maria Meyer ◽

Gabriel Rodríguez ◽

Laura Garay ◽

Roberto E. Sica ◽

...

Keyword(s):

Prognostic Factors ◽

Neurodegenerative Disorder ◽

Neuronal Damage ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Sporadic Als ◽

Bulbar Onset ◽

Als Patients ◽

Short Time ◽

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Worse prognostic factors in ALS are: (a) advanced age, (b) bulbar onset, and (c) short time between onset and diagnosis. Progesterone (PROG) has been associated with neuroprotective and promyelinating activities in injury, ischemia and degeneration of the central and peripheral nervous system. Cortisol is connected to the response to stress situations and could contribute to neuronal damage. The goals of this study were: (i) to investigate whether PROG levels are modified by ALS prognostic factors and (ii) to determine whether cortisol follows the same pattern. We determined serum steroid levels in 27 patients with sporadic ALS (sALS) and 21 controls. Both steroid hormones showed significantly increased levels in ALS patients versus controls (mean±SEM: PROG ALS vs. control: 0.54±0.05 vs. 0.39±0.04 ng/mL, p<0.05; cortisol ALS vs. control: 17.02±1.60 vs. 11.83±1.38 μg/dL, p<0.05).

Unstable control of breathing can lead to ineffective noninvasive ventilation in amyotrophic lateral sclerosis

ERJ Open Research ◽

10.1183/23120541.00099-2019 ◽

2019 ◽

Vol 5 (3) ◽

pp. 00099-2019 ◽

Cited By ~ 2

Author(s):

Jesús Sancho ◽

Enric Burés ◽

Santos Ferrer ◽

Ana Ferrando ◽

Pilar Bañuls ◽

...

Keyword(s):

Motor Neuron ◽

Noninvasive Ventilation ◽

Upper Airway ◽

Control Of Breathing ◽

Controller Gain ◽

Central Origin ◽

Als Patients ◽

Bulbar Dysfunction ◽

Upper airway obstruction with decreased central drive (ODCD) is one of the causes of ineffective noninvasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS). The aim of this study is to determine the mechanism responsible for ODCD in ALS patients using NIV.This is a prospective study that included ALS patients with home NIV. Severity of bulbar dysfunction was assessed with the Norris scale bulbar subscore; data on upper or lower bulbar motor neuron predominant dysfunction on physical examination were collected. Polysomnography was performed on every patient while using NIV and the ODCD index (ODCDI: number of ODCD events/total sleep time) was calculated. To determine the possible central origin of ODCD, controller gain was measured by inducing a hypocapnic hyperventilation apnoea. Sonography of the upper airway during NIV was performed to determine the location of the ODCD.30 patients were enrolled; three (10%) had ODCDI >5 h−1. The vast majority of ODCD events were produced during non-rapid eye movement sleep stages and were a consequence of an adduction of the vocal folds. Patients with ODCDI >5 h−1 had upper motor neuron predominant dysfunction at the bulbar level, and had greater controller gain (1.97±0.33 versus 0.91±0.36 L·min−1·mmHg−1; p<0.001) and lower carbon dioxide (CO2) reserve (4.00±0.00 versus 10.37±5.13 mmHg; p=0.043). ODCDI was correlated with the severity of bulbar dysfunction (r= −0.37; p=0.044), controller gain (r=0.59; p=0.001) and CO2 reserve (r= −0.35; p=0.037).ODCD events in ALS patients using NIV have a central origin, and are associated with instability in the control of breathing and an upper motor neuron predominant dysfunction at the bulbar level.

Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis

Cells ◽

10.3390/cells9030571 ◽

2020 ◽

Vol 9 (3) ◽

pp. 571 ◽

Cited By ~ 3

Author(s):

Emily R. Seminary ◽

Stephanie Santarriaga ◽

Lynn Wheeler ◽

Marie Mejaki ◽

Jenica Abrudan ◽

...

Keyword(s):

Stem Cells ◽

Motor Neuron ◽

Induced Pluripotent Stem Cells ◽

Motor Neurons ◽

Pluripotent Stem Cells ◽

Identical Twins ◽

Sporadic Als ◽

Induced Pluripotent ◽

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no known genetic link. As such, sporadic cases have been more difficult to model experimentally. Here, we describe the generation and differentiation of ALS induced pluripotent stem cells reprogrammed from discordant identical twins. Whole genome sequencing revealed no relevant mutations in known ALS-causing genes that differ between the twins. As protein aggregation is found in all ALS patients and is thought to contribute to motor neuron death, we sought to characterize the aggregation phenotype of the sporadic ALS induced pluripotent stem cells (iPSCs). Motor neurons from both twins had high levels of insoluble proteins that commonly aggregate in ALS that did not robustly change in response to exogenous glutamate. In contrast, established genetic ALS iPSC lines demonstrated insolubility in a protein- and genotype-dependent manner. Moreover, whereas the genetic ALS lines failed to induce autophagy after glutamate stress, motor neurons from both twins and independent controls did activate this protective pathway. Together, these data indicate that our unique model of sporadic ALS may provide key insights into disease pathology and highlight potential differences between sporadic and familial ALS.