scholarly journals Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant

1998 ◽  
Vol 95 (16) ◽  
pp. 9631-9636 ◽  
Author(s):  
Toni L. Williamson ◽  
Lucie I. Bruijn ◽  
Qinzhang Zhu ◽  
Karen L. Anderson ◽  
Scott D. Anderson ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Motor Neurons ◽  
Selective Vulnerability ◽  
Superoxide Dismutase 1 ◽  
Filament Assembly ◽  
Progression Of Disease ◽  
Familial Als ◽  
Sod1 Mutant ◽  
Lateral Sclerosis

Mutations in superoxide dismutase 1 (SOD1), the only proven cause of amyotrophic lateral sclerosis (ALS), provoke disease through an unidentified toxic property. Neurofilament aggregates are pathologic hallmarks of both sporadic and SOD1-mediated familial ALS. By deleting NF-L, the major neurofilament subunit required for filament assembly, onset and progression of disease caused by familial ALS-linked SOD1 mutant G85R are significantly slowed, while selectivity of mutant-mediated toxicity for motor neurons is reduced. In NF-L-deleted animals, levels of the two remaining neurofilament subunits, NF-M and NF-H, are markedly reduced in axons but are elevated in motor neuron cell bodies. Thus, while neither perikaryal nor axonal neurofilaments are essential for SOD1-mediated disease, the absence of assembled neurofilaments both diminishes selective vulnerability and slows SOD1G85R mutant-mediated toxicity to motor neurons.

scholarly journals Brain Protease Activated Receptor 1 Pathway: A Therapeutic Target in the Superoxide Dismutase 1 (SOD1) Mouse Model of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 21 (10) ◽  
pp. 3419
Author(s):  
Efrat Shavit-Stein ◽  
Ihab Abu Rahal ◽  
Doron Bushi ◽  
Orna Gera ◽  
Roni Sharon ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Motor Neurons ◽  
Thrombin Inhibitor ◽  
Superoxide Dismutase 1 ◽  
Motor Neuron Degeneration ◽  
Thrombin Activity ◽  
Protease Activated Receptor 1 ◽  
Sod1 Mouse ◽  
Lateral Sclerosis

Glia cells are involved in upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Protease activated receptor 1 (PAR1) pathway is related to brain pathologies. Brain PAR1 is located on peri-synaptic astrocytes, adjacent to pyramidal motor neurons, suggesting possible involvement in ALS. Brain thrombin activity in superoxide dismutase 1 (SOD1) mice was measured using a fluorometric assay, and PAR1 levels by western blot. PAR1 was localized using immunohistochemistry staining. Treatment targeted PAR1 pathway on three levels; thrombin inhibitor TLCK (N-Tosyl-Lys-chloromethylketone), PAR1 antagonist SCH-79797 and the Ras intracellular inhibitor FTS (S-trans-trans-farnesylthiosalicylic acid). Mice were weighed and assessed for motor function and survival. SOD1 brain thrombin activity was increased (p < 0.001) particularly in the posterior frontal lobe (p = 0.027) and hindbrain (p < 0.01). PAR1 levels were decreased (p < 0.001, brain, spinal cord, p < 0.05). PAR1 and glial fibrillary acidic protein (GFAP) staining decreased in the cerebellum and cortex. SOD1 mice lost weight (≥17 weeks, p = 0.047), and showed shorter rotarod time (≥14 weeks, p < 0.01). FTS 40mg/kg significantly improved rotarod scores (p < 0.001). Survival improved with all treatments (p < 0.01 for all treatments). PAR1 antagonism was the most efficient, with a median survival improvement of 10 days (p < 0.0001). Our results support PAR1 pathway involvement in ALS.

Modelling a Novel Superoxide Dismutase 1 Mutation in Motor Neurons: An Insight into Molecular Pathomechanism of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Sagar Verma ◽  
Abhishek Vats ◽  
Mandaville Gourie-Devi ◽  
Shiffali Khurana ◽  
Nirmal Kumar Ganguly ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Motor Neurons ◽  
Superoxide Dismutase 1 ◽  
Insight Into ◽  
Lateral Sclerosis

scholarly journals A neurotoxic peripherin splice variant in a mouse model of ALS

2003 ◽  
Vol 160 (6) ◽  
pp. 939-949 ◽  
Author(s):  
Janice Robertson ◽  
Mohammad M. Doroudchi ◽  
Minh Dang Nguyen ◽  
Heather D. Durham ◽  
Michael J. Strong ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Splice Variants ◽  
Superoxide Dismutase 1 ◽  
Specific Antibodies ◽  
Axonal Spheroids ◽  
Familial Als ◽  
Nif Proteins ◽  
Lateral Sclerosis

Peripherin, a neuronal intermediate filament (nIF) protein found associated with pathological aggregates in motor neurons of patients with amyotrophic lateral sclerosis (ALS) and of transgenic mice overexpressing mutant superoxide dismutase-1 (SOD1G37R), induces the selective degeneration of motor neurons when overexpressed in transgenic mice. Mouse peripherin is unique compared with other nIF proteins in that three peripherin isoforms are generated by alternative splicing. Here, the properties of the peripherin splice variants Per 58, Per 56, and Per 61 have been investigated in transfected cell lines, in primary motor neurons, and in transgenic mice overexpressing peripherin or overexpressing SOD1G37R. Of the three isoforms, Per 61 proved to be distinctly neurotoxic, being assembly incompetent and inducing degeneration of motor neurons in culture. Using isoform-specific antibodies, Per 61 expression was detected in motor neurons of SOD1G37R transgenic mice but not of control or peripherin transgenic mice. The Per 61 antibody also selectively labeled motor neurons and axonal spheroids in two cases of familial ALS and immunoprecipitated a higher molecular mass peripherin species from disease tissue. This evidence suggests that expression of neurotoxic splice variants of peripherin may contribute to the neurodegenerative mechanism in ALS.

scholarly journals ALS-Related Mutant SOD1 Aggregates Interfere with Mitophagy by Sequestering the Autophagy Receptor Optineurin

2020 ◽  
Vol 21 (20) ◽  
pp. 7525
Author(s):  
Yeong Jin Tak ◽  
Ju-Hwang Park ◽  
Hyangshuk Rhim ◽  
Seongman Kang
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cellular Cytotoxicity ◽  
Superoxide Dismutase 1 ◽  
Gene Encoding ◽  
Abnormal Protein ◽  
Mutant Sod1 ◽  
Familial Als ◽  
The Relationship ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive demise of motor neurons. One of the causes of familial ALS is the mutation of the gene encoding superoxide dismutase 1 (SOD1), which leads to abnormal protein aggregates. How SOD1 aggregation drives ALS is still poorly understood. Recently, ALS pathogenesis has been functionally implicated in mitophagy, specifically the clearance of damaged mitochondria. Here, to understand this mechanism, we investigated the relationship between the mitophagy receptor optineurin and SOD1 aggregates. We found that mutant SOD1 (mSOD1) proteins associate with and then sequester optineurin, which is required to form the mitophagosomes, to aggregates in N2a cells. Optineurin recruitment into mSOD1 aggregates resulted in a reduced mitophagy flux. Furthermore, we observed that an exogenous augmentation of optineurin alleviated the cellular cytotoxicity induced by mSOD1. Taken together, these studies demonstrate that ALS-linked mutations in SOD1 interfere with the mitophagy process through optineurin sequestration, suggesting that the accumulation of damaged mitochondria may play a crucial role in the pathophysiological mechanisms contributing to ALS.

scholarly journals Skeletal Muscle Metabolism: Origin or Prognostic Factor for Amyotrophic Lateral Sclerosis (ALS) Development?

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1449
Author(s):  
Cyril Quessada ◽  
Alexandra Bouscary ◽  
Frédérique René ◽  
Cristiana Valle ◽  
Alberto Ferri ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscle Metabolism ◽  
The Body ◽  
Energy Deficit ◽  
Acid Oxidation ◽  
Progression Of Disease ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose–fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS.

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