scholarly journals Identification of Six Novel SOD1 Gene Mutations in Familial Amyotrophic Lateral Sclerosis

1998 ◽  
Vol 25 (3) ◽  
pp. 192-196 ◽  
Author(s):  
Y. Boukaftane ◽  
J. Khoris ◽  
B. Moulard ◽  
F. Salachas ◽  
V. Meininger ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Binding Sites ◽  
Autosomal Dominant ◽  
Gene Mutations ◽  
Premature Death ◽  
Sod1 Gene ◽  
Autosomal Dominant Trait ◽  
Superoxide Dismutase Gene ◽  
Lateral Sclerosis

ABSTRACT:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature death of motor neurons. In approximately 10% of the cases the disease is inherited as autosomal dominant trait (FALS). It has been found that mutations in the Cu/Zn superoxide dismutase gene (SODl) are responsible for approximately 15% of FALS kindreds. We screened affected individuals from 70 unrelated FALS kindreds and identified 10 mutations, 6 of which are novel. Surprisingly, we have found a mutation in exon 3, which includes most of the active site loop and Zn2+ binding sites, a region where no previous SOD1 mutations have been found. Our data increase the number of different SODl mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protein.

scholarly journals Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment

2020 ◽  
Vol 9 (1) ◽  
pp. 261 ◽  
Author(s):  
Tereza Filipi ◽  
Zuzana Hermanova ◽  
Jana Tureckova ◽  
Ondrej Vanatko ◽  
Miroslava Anderova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Cell Types ◽  
In Vivo Models ◽  
Cell Therapies ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.

SOD1 gene mutations in patients with amyotrophic lateral sclerosis: Potential of method of molecular modeling

2013 ◽  
Vol 47 (5) ◽  
pp. 751-757 ◽  
Author(s):  
E. V. Lysogorskaia ◽  
A. V. Rossokhin ◽  
N. Yu. Abramycheva ◽  
M. N. Zakharova ◽  
S. N. Illarioshkin
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Molecular Modeling ◽  
Gene Mutations ◽  
Sod1 Gene ◽  
Lateral Sclerosis

SOD1 gene mutations in Italian patients with Sporadic Amyotrophic Lateral Sclerosis (ALS)

2006 ◽  
Vol 16 (11) ◽  
pp. 800-804 ◽  
Author(s):  
L. Corrado ◽  
S. D’Alfonso ◽  
L. Bergamaschi ◽  
L. Testa ◽  
M. Leone ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Gene Mutations ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Sod1 Gene ◽  
Lateral Sclerosis

Roots to start research in amyotrophic lateral sclerosis: molecular pathways and novel therapeutics for future

2015 ◽  
Vol 26 (2) ◽  
Author(s):  
Dibbanti Harikrishnareddy ◽  
Shubham Misra ◽  
Sujata Upadhyay ◽  
Manish Modi ◽  
Bikash Medhi
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Signs And Symptoms ◽  
Clinical Excellence ◽  
Premature Death ◽  
Glutamate Excitotoxicity ◽  
Severe Motor ◽  
Associated Risk Factors ◽  
Aberrant Rna ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a devastating neurological disease that rapidly progresses from mild motor symptoms to severe motor paralysis and premature death. There is currently no cure for this devastating disease; most ALS patients die of respiratory failure generally within 3–5 years from the onset of signs and symptoms. Approximately 90% of ALS cases are sporadic in nature, with no clear associated risk factors. It is reported that ALS is a complex and multifaceted neurodegenerative disease. Less is known about the key factors involved in the sporadic form of the disease. The intricate pathogenic mechanisms that target motor neurons in ALS includes oxidative stress, glutamate excitotoxicity, mitochondrial damage, protein aggregation, glia and neuroinflammation pathology, defective axonal transport, and aberrant RNA metabolism. Despite aggressive research, no therapy has been yet proven to completely reverse the core symptoms of the disease. Riluzole is the only drug approved by the Food and Drug Administration and recommended by the National Institute for Clinical Excellence so far proven to be successful against ALS and may prevent progression and extend life for a few months or so. This article provides a novel understanding in key findings of pathogenesis and interventions currently under investigation to slow disease progression in ALS.

scholarly journals A Frameshift Deletion in Peripherin Gene Associated with Amyotrophic Lateral Sclerosis

2004 ◽  
Vol 279 (44) ◽  
pp. 45951-45956 ◽  
Author(s):  
François Gros-Louis ◽  
Roxanne Larivière ◽  
Geneviève Gowing ◽  
Sandra Laurent ◽  
William Camu ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Gene Mutations ◽  
Frameshift Deletion ◽  
Nucleotide Insertion ◽  
Exon 1 ◽  
Sporadic Cases ◽  
Polymorphic Variants ◽  
Als Patients ◽  
Lateral Sclerosis

Peripherin is a neuronal intermediate filament associated with inclusion bodies in motor neurons of patients with amyotrophic lateral sclerosis (ALS). A possible peripherin involvement in ALS pathogenesis has been suggested based on studies with transgenic mouse overexpressors and with a toxic splicing variant of the mouse peripherin gene. However, the existence of peripherin gene mutations in human ALS has not yet been documented. Therefore, we screened for sequence variants of the peripherin gene (PRPH) in a cohort of ALS patients including familial and sporadic cases. We identified 18 polymorphic variants ofPRPHdetected in both ALS and age-matched control populations. Two additionalPRPHvariants were discovered in ALS cases but not in 380 control individuals. One variant consisted of a nucleotide insertion in intron 8 (PRPHIVS8–36insA), whereas the other one consisted of a 1-bp deletion within exon 1 (PRPH228delC), predicting a truncated peripherin species of 85 amino acids. Remarkably, expression of this frameshift peripherin mutant in SW13 cells resulted in disruption of neurofilament network assembly. These results suggest thatPRPHmutations may be responsible for a small percentage of ALS, cases and they provide further support of the view that neurofilament disorganization may contribute to pathogenesis.

scholarly journals Risk Factors and Emerging Therapies in Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 20 (11) ◽  
pp. 2616 ◽  
Author(s):  
Natalia Nowicka ◽  
Jakub Juranek ◽  
Judyta K. Juranek ◽  
Joanna Wojtkiewicz
Keyword(s):  
Risk Factors ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Sod1 Gene ◽  
Stem Cell Therapies ◽  
Cell Therapies ◽  
Emerging Therapies ◽  
Emerging Treatments ◽  
Phase Ii And Iii ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by a permanent degeneration of both upper and lower motor neurons. Many different genes and pathophysiological processes contribute to this disease, however its exact cause remains unclear. Therefore, it is necessary to understand this heterogeneity to find effective treatments. In this review, we focus on selected environmental and genetic risk factors predisposing to ALS and highlight emerging treatments in ALS therapy. Of numerous defective genes associated with ALS, we focus on four principal genes that have been identified as definite causes of ALS: the SOD1 gene, C9orf72, TDP-43, as well as the recently identified TBK1. We also provide up-to-date information on selected environmental factors that have historically been considered as key players in ALS development and pathogenesis. In parallel to our survey of known risk factors, we also discuss emerging ALS stem cell therapies and experimental medicines currently undergoing phase II and III clinical trials.

Role of transition metals in the pathogenesis of amyotrophic lateral sclerosis

2008 ◽  
Vol 36 (6) ◽  
pp. 1322-1328 ◽  
Author(s):  
Willianne I.M. Vonk ◽  
Leo W.J. Klomp
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Transition Metals ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Sod1 Gene ◽  
Brain And Spinal Cord ◽  
Lateral Sclerosis

ALS (amyotrophic lateral sclerosis) is a devastating progressive neurodegenerative disorder resulting in selective degeneration of motor neurons in brain and spinal cord and muscle atrophy. In approx. 2% of all cases, the disease is caused by a mutation in the Cu,Zn-superoxide dismutase (SOD1) gene. The transition metals zinc and copper regulate SOD1 protein stability and activity, and disbalance of the homoeostasis of these metals has therefore been implicated in the pathogenesis of ALS. Recent data strengthen the hypothesis that these transition metals are excellent potential targets to develop an effective therapy for 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.

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