Two papers in the July 8, 2004, issue of Neuron shed light on how a mutant form of a normally protective protein in the cells of sufferers of amyotrophic lateral sclerosis targets the ”power plants” of motor neurons, killing the neurons and ultimately resulting in paralysis and death. The culprit is a mutant form of the enzyme superoxide dismutase (SOD1), which normally protects cells from harmful reactive oxygen species. However, about 3% of people with ALS have a mutant form of the enzyme.
From Cell Press:
Tracing a killer’s path in Lou Gehrig’s disease
Two papers in the July 8, 2004, issue of Neuron shed light on how a mutant form of a normally protective protein in the cells of sufferers of amyotrophic lateral sclerosis targets the ”power plants” of motor neurons, killing the neurons and ultimately resulting in paralysis and death.
The culprit is a mutant form of the enzyme superoxide dismutase (SOD1), which normally protects cells from harmful reactive oxygen species. However, about 3% of people with ALS have a mutant form of the enzyme.
Don Cleveland and his colleagues conducted experiments in mice showing that the mutant SOD1 protein selectively migrates to the mitochondria of spinal cord neurons, where it links itself to the mitochondrial membrane.
Mitochondria are the cells’ power plants, converting glucose into chemical energy that drives cellular processes. They are also the headquarters of the cells’ ”suicide” machinery, which triggers the death of cells that are malfunctioning or no longer needed–a process called apoptosis.
”This study offers one of the first glimpses into how cells from the spinal cord may be selectively targeted for degeneration in models of ALS,” wrote the researchers.
”We propose that the universal association of SOD1 mutant exclusively within affected tissues represents the common property of these mutants that initiates a cascade of damage,” they wrote.
In a second paper, Robert H. Brown, Jr., and his colleagues shed light on a specific mechanism by which the mutant SOD1 kills spinal cord neurons once it reaches their mitochondria.
Brown and his colleagues discovered that, in both mouse and human spinal cord neurons, mutant SOD1 specifically links itself to a key mitochondrial protein, called Bcl-2, that normally suppresses the apoptotic machinery of cells. Bcl-2 is also important in maintaining the function of the mitochondrial membrane. The researchers did not find evidence of such linkage in liver cell mitochondria, hinting that, for a reason they do not yet understand, spinal cord neurons are particular targets of the mutant protein.
Such aggregation of the mutant protein with Bcl-2 could trigger the cell death machinery by either depleting Bcl-2 or even converting it into a cell death activator, concluded the researchers.
The preferential aggregation of mutant SOD1 in spinal cord mitochondria ”defines a potential Achilles’ heel that may render spinal cord cells susceptible to this mutant protein,” wrote the researchers.
Jian Liu, Concepci?n Lillo, P. Andreas Jonsson, Christine Vande Velde, Christopher M. Ward, Timothy M. Miller, Jamuna R. Subramaniam, Jeffery D. Rothstein, Stefan Marklund, Peter M. Andersen, Thomas Br?nnstr?m, Ole Gredal, Philip C. Wong, David S. Williams, and Don W. Cleveland: ”Toxicity of Familial ALS-Linked SOD1 Mutants from Selective Recruitment to Spinal Mitochondria”
Piera Pasinelli, Mary Elizabeth Belford, Niall Lennon, Brian J. Bacskai, Bradley T. Hyman, Davide Trotti, and Robert H. Brown, Jr.: ”Amyotrophic Lateral Sclerosis-Associated Mutant Proteins Bind and Aggregate with Bcl-2 in Spinal Cord Mitochondria”
