Published in the July 8, 2004 issue of the journal Neuron, the findings identify mitochondria as the focus of ALS toxicity and provide the first explanation of how a mutant protein called SOD1 that occurs in all cells in the body is damaging only to specific neuron cells. The result is ALS, a progressive degeneration of motor nerve cells in the spinal cord that leads to wasted muscles and premature death in middle-aged adults.
Found in all cells, mitochondria provide cellular energy in their role as the body's power generators. In addition, mitochondria are intricately involved in a process called apoptosis, or programmed cell death, which is the body's normal method of disposing of damaged, unwanted or unneeded cells.
"We believe that when the mutant SOD1 binds to mitochondria, it affects the ability of these components to generate cell energy," said the study's senior author, Don Cleveland, Ph.D., a UCSD professor of medicine, neurosciences, and cellular and molecular medicine, and a faculty member of the Ludwig Institute for Cancer Research.
He added that "the SOD1 may also tip the balance and induce mitochondria to send a cell death signal to the motor neurons."
In laboratory studies with tissue from animals and humans, the UCSD team determined that the mutant SOD1 ignores all other mitochondria in cells and tissue outside of the spinal cord, and binds only to the mitochondria in the large motor neurons that begin in the spinal cord and extend down the arms and legs. They found SOD1 both inside the mitochondria and coated on the mitochondria's outer components.
"However, we don't know yet which is the most damaging, the mutant protein inside the mitochondria or coated on the outside," Cleveland said. "This is part of our continuing work as we seek components to block the toxicity of SOD1 and find ways to slow the damage that occurs in ALS."
The research was supported by grants from the National Institutes of Health, the Spinal Cord Foundation, and the Bjorklund Foundation for ALS Research.
The study's first author was Jlan Liu, Ph.D., the Ludwig Institute for Cancer Research and the UCSD Departments of Neurosciences, Medicine and Cellular and Molecular Medicine. Co-authors were Concepcion Lillo, Ph.D. and David Williams, Ph.D., UCSD Department of Pharmacology; P. Andreas Jonsson, Ph.D., Stefan Marklund, M.D., and Thomas Brannstrom, M.D., Department of Medical Biosciences, Umea University Hospital, Sweden; Christine Vande Velde, Ph.D. Chrostopher M. Ward, B.S., and Timothy M. Miller, M.D., Ph.D., Ludwig Institute for Cancer Research and UCSD Departments of Neurosciences, Medicine and Cellular and Molecular Medicine; Jamuna R. Subramaniam, Ph.D., Jeffrey D. Rothstein, M.D., Ph.D., and Philip Wong, Ph.D., Department of Pathology, Johns Hopkins University School of Medicine; Peter M. Anderson, M.D., Department of Neurology, Umea University Hospital, Sweden; and Ole Gredal, M.D., Department of Neurology, Bispebjerg Hospital, Denmark.
Journal
Neuron