Over 100 mutations in Cu/Zn-superoxide dismutase (SOD1) result in familial amyotrophic lateral sclerosis. Dimer dissociation is the first step in SOD1 aggregation, and studies suggest nearly every amino acid residue in SOD1 is dynamically connected to the dimer interface. Post-translational modifications of SOD1 residues might be expected to have similar effects to mutations, but few modificati...

Mutations in superoxide dismutase 1 (SOD1) are associated with familial cases of amyotrophic lateral sclerosis (fALS). Studies in transgenic mice have suggested that wild-type (WT) SOD1 can modulate the toxicity of mutant SOD1. In the present study, we demonstrate that the effects of WT SOD1 on the age at which transgenic mice expressing mutant human SOD1 (hSOD1) develop paralysis are influence...

In mutant superoxide dismutase (SOD1)-linked amyotrophic lateral sclerosis (ALS), accumulation of misfolded mutant SOD1 in spinal cord mitochondria is thought to cause mitochondrial dysfunction. Whether mutant SOD1 is toxic per se or whether it damages the mitochondria through interactions with other mitochondrial proteins is not known. We previously identified Bcl-2 as an interacting partner o...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; survival in ALS is typically 3-5 years. No treatment extends patient survival by more than three months. Approximately 20% of familial ALS and 1-3% of sporadic ALS patients carry a mutation in the gene encoding superoxide dismutase 1 (SOD1). In a transgenic ALS mouse model expressing the mutant SOD1(G93A) protein, silenci...

The Cu- and Zn-containing superoxide dismutase 1 (SOD1) largely obtains Cu in vivo by means of the action of the Cu chaperone CCS. Yet, in the case of mammalian SOD1, a secondary pathway of activation is apparent. Specifically, when human SOD1 is expressed in either yeast or mammalian cells that are null for CCS, the SOD1 enzyme retains a certain degree of activity. This CCS-independent activit...

The antioxidant enzyme Cu,Zn superoxide dismutase (SOD1) is predominantly localized in the cytosol, but it is also found in mitochondria. Studies in yeast suggest that apoSOD1 is imported into mitochondria and trapped inside by folding and maturation, which is facilitated by its copper chaperone for SOD1 (CCS). Here, we show that in mammalian cells, SOD1 mitochondrial localization is dictated b...

Motor axon degeneration is a critical but poorly understood event leading to weakness and muscle atrophy in motor neuron diseases. Here, we investigated oxidative stress-mediated axonal degeneration in mice lacking the antioxidant enzyme, Cu,Zn superoxide dismutase (SOD1). We demonstrate a progressive motor axonopathy in these mice and show that Sod1(-/-) primary motor neurons extend short axon...

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, a fatal degenerative disorder in which motor neurons in the central nervous system (CNS) progressively deteriorate. Most cases of ALS are sporadic, but 10% are familial and mutations affecting the copper (Cu)-dependent antioxidant Cu/Zn-superoxide dismutase (SOD1) are the most common familial cause. Cu malfunct...

An increasing body of evidence suggests that mitochondrial dysfunction plays an important role in the pathogenesis of familial amyotrophic lateral sclerosis associated with "gain of function" mutations in Cu/Zn superoxide dismutase 1 (SOD1). SOD1 is mostly a cytosolic protein, but a portion of SOD1 is localized in mitochondria of patients with familial amyotrophic lateral sclerosis and transgen...

We have previously shown that a fraction of yeast copper/zinc-superoxide dismutase (SOD1) and its copper chaperone CCS localize to the intermembrane space of mitochondria. In the present study, we have focused on the mechanism by which SOD1 is partitioned between cytosolic and mitochondrial pools. Using in vitro mitochondrial import assays, we show that only a very immature form of the SOD1 pol...