Misfolded Mutant SOD1 Directly Inhibits Conductance in Mouse Model

New research uncovers what may be a primary neuron-damaging insult that occurs in an inherited form of the devastating neurodegenerative disorder, amyotrophic lateral sclerosis (ALS).  The mutant superoxide dismutase (SOD1) protein is one cause of familial ALS.  Although mechanisms underlying mutant SOD1 neurotoxicity remain uncertain, this mutant protein is associated with the cell’s mitochondria, tiny intracellular energy-producing structures.  Investigators, lead by Professor Don W. Cleveland at the University of California San Diego, report in the current issue of the scientific journal Neuron that abnormally folded mutant SOD1 interacts with voltage-dependent anion channel (VDAC1), which is located in the outer membrane of the mitochondria.

This finding sheds light into possible molecular links between mutant SOD1 mitochondrial dysfunction and spinal motor neuron degeneration of inherited ALS.  This channel controls important metabolic and energetic functions between the mitochondria and the rest of the cell.  Interestingly, this same channel has been implicated in Parkinson’s disease where studies have shown that a protein linked to the disease called Parkin interacts with this channel.

“Our evidence demonstrates that reduced VDAC1 function and correspondingly reduced mitochondrial function are direct components of intracellular damage from mutant SOD1,” says Professor Cleveland.  “The finding that VDAC1 is a target for mutant SOD1 within the nervous system provides important insight into the mechanism underlying premature degeneration and death of motor neurons.”

These studies were performed in the mutant SOD1 rats using antibodies that specifically recognize the abnormally folded mutant form of SOD1.  Investigators were able to demonstrate a reduction in conductance through this channel.  The channel conductance was not affected in liver mitochondria, and previous studies have shown that abnormally folded mutant protein does not accumulate in liver mitochondria.  This suggests that this interaction only occurs with the abnormally folded mutant protein in the affected tissues in ALS.  Chronic mitochondrial dysfunction can lead to oxidative damage and neuronal degeneration.

“This study builds on earlier findings that mitochondria are critical players in the disease mechanism; however, the new findings highlight a novel mechanism and a potential new target for the development of therapies” commented ALS Association Chief Scientist Lucie Bruijn, Ph.D.