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Mutations in superoxide dismutase 1 (SOD1) associated with familial amyotrophic lateral sclerosis induce misfolding and aggregation of the protein with the inherent propensity of mutant SOD1 to aggregate generally correlating, with a few exceptions, to the duration of illness in patients with the same mutation. One notable exception was the D101N variant,(More)
BACKGROUND Mutations in Matrin 3 [MATR3], an RNA- and DNA-binding protein normally localized to the nucleus, have been linked to amyotrophic lateral sclerosis (ALS) and distal myopathies. In the present study, we have used transient transfection of cultured cell lines to examine the impact of different disease-causing mutations on the localization of Matrin(More)
Recent studies have implicated an N-terminal caspase-6 cleavage product of mutant huntingtin (htt) as an important mediator of toxicity in Huntington's disease (HD). To directly assess the consequences of such fragments on neurologic function, we produced transgenic mice that express a caspase-6 length N-terminal fragment of mutant htt (N586) with both(More)
Co-expression of wild-type human superoxide dismutase 1 (WT-hSOD1) with ALS mutant hSOD1 accelerates disease onset relative to mice expressing only mutant protein. Here, we analyzed the effect of co-expressed WT-hSOD1 in two established mutant mouse models (L126Z and G37R), and a new model that expresses the first 102 amino acids of SOD1 with mutations at(More)
Mutations in superoxide dismutase 1 (SOD1) cause familial amyotrophic lateral sclerosis. The Cu-binding capacity of SOD1 has spawned hypotheses that implicate metal-mediated production of reactive species as a potential mechanism of toxicity. In past experiments, we have tested such hypotheses by mutating residues in SOD1 that normally coordinate the(More)
BACKGROUND Pathologic aggregates of superoxide dismutase 1 (SOD1) harboring mutations linked to familial amyotrophic lateral sclerosis (fALS) have been shown to contain aberrant intermolecular disulfide cross-links. In prior studies, we observed that intermolecular bonding was not necessary in the formation of detergent- insoluble SOD1 complexes by mutant(More)
Disruptions in metal ion homeostasis have been described in association with amyotrophic lateral sclerosis (ALS) for a number of years but the precise mechanism of involvement is poorly understood. Metal ions are especially important to familial ALS cases caused by mutations in the metalloenzyme copper-zinc superoxide dismutase (SOD1). To investigate the(More)
BACKGROUND N-terminal fragments of mutant huntingtin (htt) that terminate between residues 90-115, termed cleavage product A or 1 (cp-A/1), form intracellular and intranuclear inclusion bodies in the brains of patients with Huntington's disease (HD). These fragments appear to be proteolytic products of the full-length protein. Here, we use an HEK293 cell(More)
BACKGROUND By mechanisms yet to be discerned, the co-expression of high levels of wild-type human superoxide dismutase 1 (hSOD1) with variants of hSOD1 encoding mutations linked familial amyotrophic lateral sclerosis (fALS) hastens the onset of motor neuron degeneration in transgenic mice. Although it is known that spinal cords of paralyzed mice accumulate(More)
Mutations in superoxide dismutase 1 (SOD1) cause familial forms of amyotrophic lateral sclerosis (fALS). Disease causing mutations have diverse consequences on the activity and half-life of the protein, ranging from complete inactivity and short half-life to full activity and long-half-life. Uniformly, disease causing mutations induce the protein to misfold(More)