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 Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

2015 ◽  
Vol 113 (3) ◽  
pp. 614-619 ◽  
Author(s):  
Elizabeth A. Proctor ◽  
Lanette Fee ◽  
Yazhong Tao ◽  
Rachel L. Redler ◽  
James M. Fay ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Therapeutic Strategies ◽  
Therapeutic Interventions ◽  
Neuron Death ◽  
Motor Neuron Death ◽  
Molecular Etiology ◽  
Superoxide Dismutase Gene ◽  
Lateral Sclerosis

Since the linking of mutations in the Cu,Zn superoxide dismutase gene (sod1) to amyotrophic lateral sclerosis (ALS) in 1993, researchers have sought the connection between SOD1 and motor neuron death. Disease-linked mutations tend to destabilize the native dimeric structure of SOD1, and plaques containing misfolded and aggregated SOD1 have been found in the motor neurons of patients with ALS. Despite advances in understanding of ALS disease progression and SOD1 folding and stability, cytotoxic species and mechanisms remain unknown, greatly impeding the search for and design of therapeutic interventions. Here, we definitively link cytotoxicity associated with SOD1 aggregation in ALS to a nonnative trimeric SOD1 species. We develop methodology for the incorporation of low-resolution experimental data into simulations toward the structural modeling of metastable, multidomain aggregation intermediates. We apply this methodology to derive the structure of a SOD1 trimer, which we validate in vitro and in hybridized motor neurons. We show that SOD1 mutants designed to promote trimerization increase cell death. Further, we demonstrate that the cytotoxicity of the designed mutants correlates with trimer stability, providing a direct link between the presence of misfolded oligomers and neuron death. Identification of cytotoxic species is the first and critical step in elucidating the molecular etiology of ALS, and the ability to manipulate formation of these species will provide an avenue for the development of future therapeutic strategies.

Amyotrophic Lateral Sclerosis

2017 ◽  
Author(s):  
Laura Ferraiuolo ◽  
Stephen J. Kolb
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Molecular Basis ◽  
Biological Characteristics ◽  
Molecular Pathways ◽  
Neuron Death ◽  
Neuron Loss ◽  
Motor Neuron Death ◽  
Motor Neuron Loss ◽  
Lateral Sclerosis

An overriding mystery of ALS pathogenesis orbits around the molecular basis of selective motor neuron vulnerability and clouds our view. There are likely mechanisms involved in the initiation of motor neuron loss and mechanisms involved in the progression of motor neuron loss once initiated. Motor neuron vulnerability is likely related to the unique biological characteristics of these cells. This chapter introduces central molecular pathways that appear to be involved in the pathogenesis of ALS, and highlights why dysregulation of these mechanisms could lead to motor neuron death. Indeed, there are likely mechanisms involved in the initiation of motor neuron loss and mechanisms involved in the progression of motor neuron loss once initiated. Our task is to determine those mechanisms that are relevant to ALS pathogenesis that may be targeted therapeutically to prevent onset and/or halt progression.

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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