SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity

AbstractMutations in superoxide dismutase 1 gene (SOD1) are linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder predominantly affecting upper and lower motor neurons. The clinical phenotype of ALS shows inter- and intrafamilial heterogeneity. The aim of the study was to analyze the relations between individual SOD1 mutations and the clinical presentation using in silico methods to assess the SOD1 mutations severity. We identified SOD1 causative variants in a group of 915 prospectively tested consecutive Polish ALS patients from a neuromuscular clinical center, performed molecular modeling of mutated SOD1 proteins and in silico analysis of mutation impact on clinical phenotype and survival analysis of associations between mutations and hazard of clinical end-points. Fifteen SOD1 mutations were identified in 21.1% familial and 2.3% sporadic ALS cases. Their effects on SOD1 protein structure and functioning inferred from molecular modeling and in silico analyses correlate well with the clinical data. Molecular modeling results support the hypothesis that folding intermediates rather than mature SOD1 protein give rise to the source of cytotoxic conformations in ALS. Significant associations between type of mutation and clinical end-points were found.

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IBD analysis of Australian amyotrophic lateral sclerosis SOD1-mutation carriers identifies five founder events and links sporadic cases to existing ALS families

10.1101/685925 ◽

2019 ◽

Cited By ~ 2

Author(s):

Lyndal Henden ◽

Natalie A. Twine ◽

Piotr Szul ◽

Emily P. McCann ◽

Garth A. Nicholson ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Sporadic Case ◽

Sporadic Als ◽

Disease Penetrance ◽

Sporadic Cases ◽

Familial Als ◽

Founder Events ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by the loss of upper and lower motor neurons resulting in paralysis and eventual death. Approximately 10% of ALS cases have a family history of disease, while the remaining cases present as apparently sporadic. Heritability studies suggest a significant genetic component to sporadic ALS, and although most sporadic cases have an unknown genetic etiology, some familial ALS mutations have also been found in sporadic cases. This suggests that some sporadic cases may be unrecognised familial cases with reduced disease penetrance. Identifying a familial basis of disease in apparently sporadic ALS cases has significant genetic counselling implications for immediate relatives. A powerful strategy to uncover a familial link is identity-by-descent (IBD) analysis which detects genomic regions that have been inherited from a common ancestor. We performed IBD analysis on 90 Australian familial ALS cases from 25 families and three sporadic ALS cases, each of whom carried one of three SOD1 mutations (p.I114T, p.V149G and p.E101G). We identified five unique haplotypes that carry these mutations in our cohort, indicative of five founder events. This included two different haplotypes that carry SOD1 p.I114T, where one haplotype was present in one sporadic case and 20 families, while the second haplotype was found in the remaining two sporadic cases and one family, thus linking these familial and sporadic cases. Furthermore, we linked two families that carry SOD1 p.V149G and found that SOD1 p.E101G arose independently in each family that carries this mutation.

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Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated

Scientific Reports ◽

10.1038/s41598-021-97928-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tanisha Singh ◽

Yuanyuan Jiao ◽

Lisa M. Ferrando ◽

Svitlana Yablonska ◽

Fang Li ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mitochondrial Dysfunction ◽

Motor Neurons ◽

Protein Import ◽

Neurodegenerative Disorder ◽

Mitochondrial Protein ◽

Neural Progenitors ◽

Developmentally Regulated ◽

Sporadic Als ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Mitochondria are essential for neuronal survival but the developmental timing and mechanistic importance of mitochondrial dysfunction in sporadic ALS (sALS) neurons is not fully understood. We used human induced pluripotent stem cells and generated a developmental timeline by differentiating sALS iPSCs to neural progenitors and to motor neurons and comparing mitochondrial parameters with familial ALS (fALS) and control cells at each developmental stage. We report that sALS and fALS motor neurons have elevated reactive oxygen species levels, depolarized mitochondria, impaired oxidative phosphorylation, ATP loss and defective mitochondrial protein import compared with control motor neurons. This phenotype develops with differentiation into motor neurons, the affected cell type in ALS, and does not occur in the parental undifferentiated sALS cells or sALS neural progenitors. Our work demonstrates a developmentally regulated unifying mitochondrial phenotype between patient derived sALS and fALS motor neurons. The occurrence of a unifying mitochondrial phenotype suggests that mitochondrial etiology known to SOD1-fALS may applicable to sALS. Furthermore, our findings suggest that disease-modifying treatments focused on rescue of mitochondrial function may benefit both sALS and fALS patients.

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Amyotrophic Lateral Sclerosis – Clinical Features, Pathophysiology and Management

European Neurological Review ◽

10.17925/enr.2013.08.01.38 ◽

2012 ◽

Vol 8 (1) ◽

pp. 38 ◽

Cited By ~ 1

Author(s):

Christophe Coupé ◽

Paul H Gordon ◽

◽

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Muscle Protein ◽

Age Related ◽

Sporadic Als ◽

Energetic Balance ◽

Environmental Causes ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot 145 years ago, is an age-related neurodegenerative disorder that leads to destruction of motor neurons. The disease begins focally in the central nervous system then spreads inexorably. The clinical diagnosis, defined by progressive upper and lower motor neuron findings, is confirmed by electromyogram. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of progressive weakness and respiratory failure less than 3 years from symptom onset. Like other neurodegenerative diseases, ALS is thought to have genetic and environmental causes. Five to 10 % of cases are inherited. Genetic factors, age, tobacco use and athleticism may contribute to sporadic ALS, but major causes are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. One medication, riluzole, which was approved in 1996, prolongs survival by several months. Numerous ensuing clinical trials have been negative. Researchers currently aim to slow disease progression by targeting known pathophysiological pathways. Approaches under examination are directed at muscle protein, energetic balance, cell replacement and protein aggregation. Until the causes and more robust neuroprotective agents are identified, symptomatic therapies can help improve expectancy and quality of life. Palliative care ensures dignity in advanced stages.

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The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

Journal of Personalized Medicine ◽

10.3390/jpm11070671 ◽

2021 ◽

Vol 11 (7) ◽

pp. 671

Author(s):

Oihane Pikatza-Menoio ◽

Amaia Elicegui ◽

Xabier Bengoetxea ◽

Neia Naldaiz-Gastesi ◽

Adolfo López de Munain ◽

...

Keyword(s):

Skeletal Muscle ◽

Amyotrophic Lateral Sclerosis ◽

Muscle Tissue ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Disease Onset ◽

Fine Tuning ◽

Current State ◽

The Central Nervous System ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

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Pulmonary function in patients with Amyotrophic Lateral Sclerosis at disease onset

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2012.146 ◽

2015 ◽

Vol 77 (3-4) ◽

Author(s):

B. Chandrasoma ◽

D. Balfe ◽

T. Naik ◽

A. Elsayegh ◽

M. Lewis ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Pulmonary Function ◽

Muscle Weakness ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Pulmonary Function Tests ◽

Disease Onset ◽

Group Versus ◽

Combination Methods ◽

Lateral Sclerosis

Background. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Deteriorating pulmonary function as a reflection of progressive respiratory muscle weakness is a common feature, accounting for the majority of deaths. The aim of the study was to describe a trend in initial pulmonary function tests (PFT) of Amyotrophic Lateral Sclerosis (ALS) patients, in addition, differentiating between the types of disease onset, bulbar, limb muscle, and a combination. Methods. Initial PFT were gathered from 32 consecutive patients in our clinic with the diagnosis of ALS, they were categorized by the type of disease onset. Values obtained were referenced to the 95% confidence limits for normality. Results. There was evidence of significant reductions in both the FEV1 (64.7% predicted) and FVC (61.2%), with preservation of the FEV1/FVC (81.7%). The MVV was significantly reduced(43%). Total lung capacity was 93.2%, the residual volumes was increased at 145.7%. Subgroup analysis failed to show significant differences between types of disease onset. In the bulbar onset group (versus the limb group) there was a trend for the MVV to be further reduced (p=0.15) and the RV to be higher (157.4% versus 135.9%, P=0.24). Conclusions. ALS is a devastating disease that invariably leads to respiratory failure. Abnormal spirometric variables such as the FVC and MVV, likely reflect inspiratory muscle weakness and increased RV likely reflect expiratory muscle weakness. The type of disease onset did not result in a different pattern of PFT abnormalities.

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Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons

Science Advances ◽

10.1126/sciadv.aat5847 ◽

2018 ◽

Vol 4 (10) ◽

pp. eaat5847 ◽

Cited By ~ 66

Author(s):

Tatsuya Osaki ◽

Sebastien G. M. Uzel ◽

Roger D. Kamm

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Unit ◽

Motor Neurons ◽

Neuromuscular Junctions ◽

Research Effort ◽

Muscle Contractions ◽

Drug Candidates ◽

Chip Technology ◽

Sporadic Als ◽

Lateral Sclerosis

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. Each tissue was cultured in a different compartment of a microfluidic device. Axon outgrowth formed neuromuscular junctions on the muscle fiber bundles. Light was used to activate muscle contraction, which was measured on the basis of pillar deflections. Compared to a non-ALS motor unit, the ALS motor unit generated fewer muscle contractions, there was MN degradation, and apoptosis increased in the muscle. Furthermore, the muscle contractions were recovered by single treatments and cotreatment with rapamycin (a mechanistic target of rapamycin inhibitor) and bosutinib (an Src/c-Abl inhibitor). This recovery was associated with up-regulation of autophagy and degradation of TAR DNA binding protein–43 in the MNs. Moreover, administering the drugs via an endothelial cell barrier decreased the expression of P-glycoprotein (an efflux pump that transports bosutinib) in the endothelial cells, indicating that rapamycin and bosutinib cotreatment has considerable potential for ALS treatment. This ALS-on-a-chip and optogenetics technology could help to elucidate the pathogenesis of ALS and to screen for drug candidates.

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In silico analysis of PFN1 related to amyotrophic lateral sclerosis

PLoS ONE ◽

10.1371/journal.pone.0215723 ◽

2019 ◽

Vol 14 (6) ◽

pp. e0215723

Author(s):

Gabriel Rodrigues Coutinho Pereira ◽

Giovanni Henrique Almeida Silva Tellini ◽

Joelma Freire De Mesquita

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

In Silico ◽

In Silico Analysis ◽

Silico Analysis ◽

Lateral Sclerosis

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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):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neurons ◽

New Drugs ◽

Small Interfering Rnas ◽

Altered Expression ◽

Sporadic Als ◽

Induced Pluripotent ◽

Lateral Sclerosis

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.

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Pathological Roles of Wild-Type Cu, Zn-Superoxide Dismutase in Amyotrophic Lateral Sclerosis

Neurology Research International ◽

10.1155/2012/323261 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

Yoshiaki Furukawa

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Superoxide Dismutase ◽

Motor Neurons ◽

Wild Type ◽

Sporadic Als ◽

Familial Form ◽

Recent Developments ◽

Lateral Sclerosis

Dominant mutations in a Cu, Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS). While it remains controversial how SOD1 mutations lead to onset and progression of the disease, manyin vitroandin vivostudies have supported a gain-of-toxicity mechanism where pathogenic mutations contribute to destabilizing a native structure of SOD1 and thus facilitate misfolding and aggregation. Indeed, abnormal accumulation of SOD1-positive inclusions in spinal motor neurons is a pathological hallmark in SOD1-related familial ALS. Furthermore, similarities in clinical phenotypes and neuropathology of ALS cases with and without mutations insod1gene have implied a disease mechanism involving SOD1 common to all ALS cases. Although pathogenic roles of wild-type SOD1 in sporadic ALS remain controversial, recent developments of novel SOD1 antibodies have made it possible to characterize wild-type SOD1 under pathological conditions of ALS. Here, I have briefly reviewed recent progress on biochemical and immunohistochemical characterization of wild-type SOD1 in sporadic ALS cases and discussed possible involvement of wild-type SOD1 in a pathomechanism of ALS.

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Sympathetic Hyperactivity and Sympathovagal Imbalance in Amyotrophic Lateral Sclerosis

European Neurological Review ◽

10.17925/enr.2013.08.01.46 ◽

2012 ◽

Vol 8 (1) ◽

pp. 46 ◽

Cited By ~ 12

Author(s):

Toshio Shimizu ◽

Keyword(s):

Heart Rate ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Hypertensive Crisis ◽

Individual Treatment ◽

Sympathetic Hyperactivity ◽

Sympathovagal Imbalance ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with progressive loss of upper and lower motor neurons. Autonomic nervous abnormalities, including sympathetic hyperactivity and sympathovagal imbalance, have been found in both early and advanced stages of ALS. In early stage, the dysfunction may be subclinical. Occasionally, elevated blood pressure or heart rate and increased sweating may be observed. In advanced stage when ventilators are required, the sympathetic hyperactivity may lead to hypertensive crisis without counter-regulation of heart rate, followed by the consecutive circulatory collapse, known as the ‘autonomic storm’. The symptoms of ‘autonomic storm’ are similar to that of ‘baroreflex failure’, and ‘autonomic storm’ indicates poor prognosis and may result in sudden death. Careful evaluation and individual treatment are strongly suggested, although appropriate therapeutic approaches have not been established. Causative central nervous lesions remain to be elucidated, although the limbic system may be involved. The autonomic dysfunction further supports the concept that ALS is a multisystem-degenerative disease.

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