Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Abstract

A growing body of evidence suggests that mitochondrial dysfunctions play a crucial role in the pathogenesis of various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting both upper and lower motor neurons. Although ALS is predominantly a sporadic disease, approximately 10% of cases are familial. The most frequent familial form is caused by mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD1). A dominant toxic gain of function of mutant SOD1 has been considered as the cause of the disease and mitochondria are thought to be key players in the pathogenesis. However, the exact nature of the link between mutant SOD1 and mitochondrial dysfunctions remains to be established. Here, we briefly review the evidence for mitochondrial dysfunctions in familial ALS and discuss a possible link between mutant SOD1 and mitochondrial dysfunction.

Bioenergetic markers in skin fibroblasts of sporadic amyotrophic lateral sclerosis and progressive lateral sclerosis patients

“…This is consistent with evidence of mitochondrial dysfunction in ALS (reviewed in 3–5 ). However, while mitochondrial function has been investigated in familial ALS with SOD1 mutations, energy metabolism in sporadic ALS (sALS) is largely unexplored.…”

A novel SOD1-ALS mutation separates central and peripheral effects of mutant SOD1 toxicity

“…Mitochondrial dysfunction has been identified as one of the earliest defects in motor neurons of transgenic SOD1 mice and it has been suggested that mitochondrial dysfunction may play a pivotal role in motor neuron degeneration in ALS (39). We therefore analysed the mitochondrial membrane potential (Δ ψ m ) of embryonic motor neurons.…”

Early Steps in Oxidation-Induced SOD1 Misfolding: Implications for Non-Amyloid Protein Aggregation in Familial ALS

“…[62][63][64]76 Additionally, cellular concentrations of oxidized glutathione are expected to rise as a result of mounting oxidative stress, possibly leading to glutathionylation of SOD1 at C111 -a posttranslational modification detected previously in SOD1 from human erythrocytes and found to destabilize the SOD1 dimer. 77,78 Computational simulations have suggested that dimer dissociation, which is expected to contribute to monomer destabilization, may occur via an intermediate stabilized by glutathionylation of C111, though the fact that this intermediate could be observed in the short time frame of these simulations (approximately 100 ns) makes it highly improbable that this species is equivalent to any of the long-lived intermediates observed in the present study.…”