scholarly journals Genetics of familial amyotrophic lateral sclerosis

2021 ◽  
Vol 20 (3) ◽  
pp. 193-202
Author(s):  
A. V. Savinova ◽  
N. A. Shnayder ◽  
R. F. Nasyrova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Molecular Genetic ◽  
Glutamate Excitotoxicity ◽  
Genetic Diagnostics ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Neuron Death ◽  
Pathogenetic Mechanisms ◽  
Motor Neuron Death ◽  
Molecular Genetic Diagnostics ◽  
Lateral Sclerosis

To analyze results of the studies covering modern scientific views on the genetics of familial amyotrophic lateral sclerosis (FALS).We searched for full-text publications containing the key words “amyotrophic lateral sclerosis”, “FALS”, and “genetics” in the literature for the past 10 years in both Russian and English in eLibrary, PubMed, Web of Science, and OMIM databases. In addition, the review includes earlier publications of historical interest.This review summarizes all existing information on four most widespread genes associated with FALS: SOD1, TARDBP, FUS, and C9ORF72. The review also describes the functions of these genes and possible pathogenetic mechanisms of motor neuron death in amyotrophic lateral sclerosis (ALS), such as mitochondrial dysfunction, oxidative stress, glutamate excitotoxicity, damage to axonal transport components, and pathological neurofilament aggregation.As modern methods of molecular genetic diagnostics evolve, our knowledge about multifactorial FALS genetics expands. This information should be taken into consideration in clinical practice of neurologists. Information about the genes associated with ALS and understanding of particular pathogenetic mechanisms of the disease play a key role in the development of effective therapeutic strategies.

scholarly journals Amyotrophic Lateral Sclerosis: A Focus on Disease Progression

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Ana C. Calvo ◽  
Raquel Manzano ◽  
Deise M. F. Mendonça ◽  
María J. Muñoz ◽  
Pilar Zaragoza ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Molecular Targets ◽  
Therapeutic Strategies ◽  
Molecular Pathways ◽  
Neuron Death ◽  
Parkinson’S Diseases ◽  
Wide Range ◽  
Motor Neuron Death ◽  
Lateral Sclerosis ◽  
Potential Biomarkers

Since amyotrophic lateral sclerosis (ALS) was discovered and described in 1869 as a neurodegenerative disease in which motor neuron death is induced, a wide range of biomarkers have been selected to identify therapeutic targets. ALS shares altered molecular pathways with other neurodegenerative diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. However, the molecular targets that directly influence its aggressive nature remain unknown. What is the first link in the neurodegenerative chain of ALS that makes this disease so peculiar? In this review, we will discuss the progression of the disease from the viewpoint of the potential biomarkers described to date in human and animal model samples. Finally, we will consider potential therapeutic strategies for ALS treatment and future, innovative perspectives.

scholarly journals Disulfide Bond Mediates Aggregation, Toxicity, and Ubiquitylation of Familial Amyotrophic Lateral Sclerosis-linked Mutant SOD1

2007 ◽  
Vol 282 (38) ◽  
pp. 28087-28095 ◽  
Author(s):  
Jun-ichi Niwa ◽  
Shin-ichi Yamada ◽  
Shinsuke Ishigaki ◽  
Jun Sone ◽  
Miho Takahashi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disulfide Bond ◽  
Disulfide Bonds ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Neuron Death ◽  
Mutant Sod1 ◽  
Intermolecular Disulfide Bonds ◽  
High Molecular Weight Aggregate ◽  
Lateral Sclerosis

Mutations in the Cu/Zn-superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS) through the gain of a toxic function; however, the nature of this toxic function remains largely unknown. Ubiquitylated aggregates of mutant SOD1 proteins in affected brain lesions are pathological hallmarks of the disease and are suggested to be involved in several proposed mechanisms of motor neuron death. Recent studies suggest that mutant SOD1 readily forms an incorrect disulfide bond upon mild oxidative stress in vitro, and the insoluble SOD1 aggregates in spinal cord of ALS model mice contain multimers cross-linked via intermolecular disulfide bonds. Here we show that a non-physiological intermolecular disulfide bond between cysteines at positions 6 and 111 of mutant SOD1 is important for high molecular weight aggregate formation, ubiquitylation, and neurotoxicity, all of which were dramatically reduced when the pertinent cysteines were replaced in mutant SOD1 expressed in Neuro-2a cells. Dorfin is a ubiquityl ligase that specifically binds familial ALS-linked mutant SOD1 and ubiquitylates it, thereby promoting its degradation. We found that Dorfin ubiquitylated mutant SOD1 by recognizing the Cys6- and Cys111-disulfide cross-linked form and targeted it for proteasomal degradation.

Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Taide Wang ◽  
Doris Tomas ◽  
Nirma D. Perera ◽  
Brittany Cuic ◽  
Sophia Luikinga ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Neuron Death ◽  
Motor Neuron Death ◽  
Lateral Sclerosis
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