Is ALS a Disease of Clogged Mitochondria?

Don Cleveland has been supported by Packard Center grants. He is presently a Packard Center collaborator in the P2ALS program.

The misfolded enzyme that causes some kinds of amyotrophic lateral sclerosis poisons motor neurons by plugging up pores in their mitochondria, report researchers from the University of California, San Diego, in the August 26 issue of Neuron. Mutations in superoxide dismutase 1 (SOD1) are responsible for some cases of inherited ALS, and first author Adrian Israelson and colleagues from Don Cleveland's laboratory used rats and mice carrying these mutations to show that the mutant protein shuts down the voltage-gated anion channel VDAC1, also called mitochondrial porin. With that portal locked, less ADP gets into the mitochondria, so they produce less ATP, and that energy loss could damage cells, the authors suggest.

The scientists knew mutant SOD1 interacted with the outer mitochondrial membrane (Vande Velde et al., 2008), so they sought specific proteins in that membrane that bind with the dismutase. This becomes particularly relevant given the importance of mitochondria in both energy metabolism and apoptosis regulation, wrote Mohanish Deshmukh of the University of North Carolina in Chapel Hill, who was not involved in the study, in an e-mail to ARF. VDAC1 transports nucleotides as well as ions across the mitochondrial membrane, and is also involved in regulating apoptosis. The interaction between mutant SOD1 and VDAC1 seems to happen specifically in the spinal cord, perhaps explaining why spinal motor neurons are particularly susceptible to ALS pathology.