Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1.

  title={Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1.},
  author={Lucie I. Bruijn and Megan K. Houseweart and Shinsuke Kato and Kelsi L. Anderson and Scott D Anderson and Eisaku Ohama and Andrew G. Reaume and Richard W. Scott and Don W. Cleveland},
  volume={281 5384},
Analysis of transgenic mice expressing familial amyotrophic lateral sclerosis (ALS)-linked mutations in the enzyme superoxide dismutase (SOD1) have shown that motor neuron death arises from a mutant-mediated toxic property or properties. In testing the disease mechanism, both elimination and elevation of wild-type SOD1 were found to have no effect on mutant-mediated disease, which demonstrates that the use of SOD mimetics is unlikely to be an effective therapy and raises the question of whether… 

Interaction between Familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 Mutants and the Dynein Complex*

A direct “gain-of-interaction” between mutant S OD1 and dynein is demonstrated, which may provide insights into the mechanism by which mutant SOD1 could contribute to a defect in retrograde axonal transport or other dyneIn functions.

Transgenic mouse models of amyotrophic lateral sclerosis.

Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase‐1 mutation

  • N. Shibata
  • Biology
    Neuropathology : official journal of the Japanese Society of Neuropathology
  • 2001
Transgenic mice carrying small transgene copy numbers of mutant SOD1 would provide a beneficial animal model for S OD1 mutant familial ALS and contribute to elucidating the pathomechanism of this disease and establishing new therapeutic agents.

An examination of wild-type SOD1 in modulating the toxicity and aggregation of ALS-associated mutant SOD1

It is shown that regardless of whether WT SOD1 changes the course of disease, both WT and mutant hSOD1 accumulate as detergent-insoluble aggregates in symptomatic mice expressing both proteins, and that complex interactions with the mutant protein may influence the formation of aggregates and inclusion bodies generated by mutant S OD1.

Fibrillar Inclusions and Motor Neuron Degeneration in Transgenic Mice Expressing Superoxide Dismutase 1 with a Disrupted Copper-Binding Site

Transgenic mice that express human SOD1 that encodes disease-linked mutations at two of the four histidine residues that are crucial for the coordinated binding of copper develop motor neuron disease, and these data are consistent with the hypothesis that the aberrant folding/aggregation of mutant S OD1 is a prominent feature in the pathogenesis of motor neurons disease.

Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria.

  • H. DengYong Shi T. Siddique
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2006
Findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders, and rational therapy can now be developed and tested.

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

Global, age-dependent changes in gene expression from rodent models of inherited ALS caused by dominant mutations in superoxide-dismutase 1 (SOD1) identified by using gene arrays and RNAs isolated from purified embryonic and adult motor neurons identified a set of targets for therapies for inherited ALS.

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.

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.

Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.

Mutations of human Cu,Zn superoxide dismutase (SOD) are found in about 20 percent of patients with familial amyotrophic lateral sclerosis (ALS). Expression of high levels of human SOD containing a

Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase.

Single-site mutants in the Cu,Zn superoxide dismutase (SOD) gene (SOD1) occur in patients with the fatal neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). Complete screening

Altered Reactivity of Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis

Results suggest that oxidative reactions catalyzed by mutant CuZnSOD enzymes initiate the neuropathologic changes in FALS.

Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury

The creation and characterization of mice completely deficient for SOD1 indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury.

Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis.

It is reported here that high expression of this altered gene in the central nervous systems of transgenic mice is associated with an age-related rapidly progressive decline of motor function accompanied by degenerative changes of motoneurons within the spinal cord, brain stem, and neocortex, indicating a causative relationship between altered SOD activity and motoneuron degeneration.

Increased 3‐nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation

The results suggest that the gain‐of‐function of at least one mutant SOD1 associated with FALS involves increased protein nitration and oxidative damage, which may play a role in neuronal degeneration.

Chaperone-facilitated copper binding is a property common to several classes of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants.

The demonstration that shows that all mutants tested do bind copper under physiologic conditions supports a mechanism of SOD1 mutant-mediated disease arising from aberrant copper-mediated chemistry catalyzed by less tightly folded (and hence less constrained) mutant enzymes.

Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.