Redox system expression in the motor neurons in amyotrophic lateral sclerosis (ALS): immunohistochemical studies on sporadic ALS, superoxide dismutase 1 (SOD1)-mutated familial ALS, and SOD1-mutated ALS animal models

2005 ◽  
Vol 110 (2) ◽  
pp. 101-112 ◽  
Author(s):  
Shinsuke Kato ◽  
Masako Kato ◽  
Yasuko Abe ◽  
Tomohiro Matsumura ◽  
Takeshi Nishino ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Animal Models ◽  
Motor Neurons ◽  
Redox System ◽  
Superoxide Dismutase 1 ◽  
Sporadic Als ◽  
Familial Als ◽  
Immunohistochemical Studies ◽  
Lateral Sclerosis

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

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
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.

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

2019 ◽  
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.

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.

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