Neuron doi:10.1016/j.neuron.2010.07.019 (2010)

In some inherited forms of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), the culprit is a mutated gene that encodes the enzyme SOD1. What hasn't been clear is how this molecule causes motor neurons in the brain and spinal cord to die.

Don Cleveland at the University of California, San Diego, and his colleagues show that a misfolded version of SOD1 binds to a protein channel in the outer membrane of mitochondria, the cell's energy-generating organelles. This protein, VDAC1, regulates the movement of ions and other molecules across the mitochondrial membrane.

The team isolated VDAC1 from normal rats and showed that mutated SOD1 binds to it, lowering VDAC1's electrical conductance, which indicates a hampered flow of ions through the channel. In addition, mitochondria from rats engineered to carry a human mutant SOD1 gene took up less ADP, a molecule needed for cellular respiration. Such impairments, the authors suggest, lead to neuronal damage.