Superoxide dismutase and neurofilament transgenic models of amyotrophic lateral sclerosis

Morrison, Brett M.; Morrison, John H.; Gordon, Jon W.

doi:10.1002/(sici)1097-010x(199809/10)282:1/2<32::aid-jez7>3.0.co;2-o

Cited by 22 publications

(6 citation statements)

References 88 publications

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“…In the MOG peptide-EAE mice, we have previously shown that the proportion of motor neurons that displayed perikaryal hypoP-NF-H immunoreactivity falls to a lower level than in control mice by day 21 post-MOG peptide [11]. We now show that in those mice with the greatest clinical deficits, occasional motor neurons show accumulations of perikaryal hyperP-NF-H immunoreactivity like those observed in humans with amyotrophic lateral sclerosis [45,48,50] and mice expressing a familial amyotrophic lateral sclerosis mutant superoxide dismutase transgene [51]. However, this was not a consistent finding and should not replace the use of antibodies recognizing hypo-P-NF-H which consistently detects perturbations in both axons and perikarya in our paradigm (this paper and Ref.…”

Section: Discussionmentioning

confidence: 99%

Enhanced visualization of axonopathy in EAE using thy1-YFP transgenic mice

Bannerman

Hahn²

2007

Journal of the Neurological Sciences

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Section: Discussionmentioning

confidence: 99%

Enhanced visualization of axonopathy in EAE using thy1-YFP transgenic mice

Bannerman

Hahn²

2007

Journal of the Neurological Sciences

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“…Abnormal accumulation of intermediate filaments (IF) in the perikarya and proximal axons of motor neurons is a common pathological hallmark of ALS, suggesting that abnormalities in neurofilament organization may be involved in the pathogenesis of ALS (180). Neurofilaments are the principal intermediate filament type expressed by motor neurons.…”

Section: Neurofilamentsmentioning

confidence: 99%

Genetic epidemiology of amyotrophic lateral sclerosis

2003

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Amyotrophic lateral sclerosis (ALS) is a late onset, rapidly progressive and ultimately fatal neurological disorder, caused by the loss of motor neurons in the brain and spinal cord. Familial aggregation of ALS, with an age-dependent but high penetrance, is a major risk factor for ALS. Familial ALS (FALS) is clinically and genetically heterogeneous. Three genes and linkage to four additional gene loci have been identified so far and may either predominantly lead to ALS (ALSI-ALS6) or cause multisystem neurodegeneration with ALS as an occasional symptom (tauopathies, ALS-dementia complex). This review presents a tentative classification of the "major" ALS genes and ALS "susceptibility" genes, that may act as susceptibility factors for neurodegeneration in interaction with other genetic or environmental risk factors. Considering that mutations in ALS genes explain approximately 10% of familial as well as sporadic ALS, and most remaining cases of the discase are thought to result form the interaction of several genes and environmental factors, ALS is a paradigm for multifactorial discases.

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“…In addition to the normal catalytic function of SOD1, there is evidence for a gain-of-function toxicity of SOD1 upon mutation. , Proteinaceous inclusions rich in mutant SOD1 are in tissues of ALS-SOD1 transgenic mice and ALS patients and in cell-culture models. , The fibrils or insoluble inclusions in ALS, however, are unlikely to be toxic because they arise in a relatively late stage of the disease . The ALS-inducing SOD1 mutants manifest a common shift of the folding equilibrium toward denatured and partially unfolded apo monomers, either disrupting the dimer interface, perturbing the monomer structure, or compromising the formation of mature (e.g., holo, disulfide-bonded) dimers. − Extensive studies show that the immature forms of SOD1, obtainable through intramolecular disulfide reduction, metal-ion removal, , heating, , and chemical induction, , readily form aggregates under physiological conditions, possibly owing to a decrease in the native SOD1 stability and/or an increase in the unfolding rates.…”

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confidence: 99%

Trifluoroethanol Partially Unfolds G93A SOD1 Leading to Protein Aggregation: A Study by Native Mass Spectrometry and FPOP Protein Footprinting

et al. 2020

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Misfolding of Cu, Zn superoxide dismutase (SOD1) variants may lead to protein aggregation and ultimately amyotrophic lateral sclerosis (ALS). The mechanism and protein conformational changes during this process are complex and remain unclear. To study SOD1 variants aggregation at the molecular level and in solution, we chemically induced aggregation of a mutant variant (G93A SOD1) with trifluoroethanol (TFE) and used both native mass spectrometry (MS) to analyze the intact protein and Fast Photochemical Oxidation of Proteins (FPOP) to characterize the structural changes induced by TFE. We found partially unfolded G93A SOD1 monomers prior to oligomerization and identified regions of the N-terminus, C-terminus, and strands β5, β6 accountable for the partial unfolding. We propose that exposure of hydrophobic interfaces of these unstructured regions serves as a precursor to aggregation. Our results provide a possible mechanism and molecular basis for ALS-linked SOD1 misfolding and aggregation.

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Superoxide dismutase and neurofilament transgenic models of amyotrophic lateral sclerosis

Cited by 22 publications

References 88 publications

Enhanced visualization of axonopathy in EAE using thy1-YFP transgenic mice

Enhanced visualization of axonopathy in EAE using thy1-YFP transgenic mice

Genetic epidemiology of amyotrophic lateral sclerosis

Trifluoroethanol Partially Unfolds G93A SOD1 Leading to Protein Aggregation: A Study by Native Mass Spectrometry and FPOP Protein Footprinting

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