Although amyotrophic lateral sclerosis (ALS) is linked to mutations in a particular gene, how these mutations cause disease symptoms has been unclear. Motor neurons secrete a mutant protein produced from this gene, setting off a chain of events that leads to cell death, reports a paper in the January issue of Nature Neuroscience.
ALS (or Lou Gehrig's disease) leads to paralysis from the death of motor neurons in the spinal cord and brainstem. It is incurable, and patients typically die within three to five years of disease onset. Only 5-10% of ALS cases are inherited, but some such patients have mutations in the gene that encodes a protein called superoxide dismutase (SOD1), an antioxidant enzyme.
Most of our current knowledge about ALS comes from analysis of mice with mutations of the SOD1 gene. In these mice, in addition to the motor neuron dysfunction, non-neuronal cells -- such as microglia -- also contribute to disease development. Jean-Pierre Julien and colleagues now suggest how microglia may contribute to disease development. They find that mutant SOD1 in motor neurons can bind to chromogranins, a family of proteins stored in secretory vesicles in neurons and microglia. When these secretory vesicles release their contents, mutant SOD1 is released into the extracellular space and binds to microglia, causing these cells in turn to release cell death-inducing molecules such as nitric oxide, which trigger motor neuron death. These results therefore provide a better understanding of how ALS symptoms develop by describing how SOD1 mutation can lead to motor neuron death.
Jean-Pierre Julien (Laval University, Montreal, Canada)
Additional contact for comment on paper:
Michael Sendtner (University of Wuerzburg, Germany)
Abstract available online.
(C) Nature Neuroscience press release.
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