Nerve Cells' Powerhouse
"Clogged" In Lou Gehrig's Disease
July 19, 2004
By studying rodent models of
the relatively rare inherited form of Lou Gehrig's disease and tissue
samples from a patient with the condition, scientists have discovered the
first evidence that damage to nerve cell powerhouses is directly responsible
for these cells' death. The findings appear in the July 9 issue of Neuron.
The research team from the University of California San Diego, Johns Hopkins
and elsewhere discovered that dysfunctional proteins clog the transport
system that brings vital substances into mitochondria, the tiny organelles
that provide energy to cells. This mitochondrial damage occurs in
muscle-controlling nerve cells, the researchers report, helping explain the
selective nature of inherited amyotrophic lateral sclerosis (ALS), or Lou
Gehrig's disease.
"Mitochondria don't look normal in motor neurons in animal models of ALS and
in patients with ALS, but this is the first study that links ALS and a
specific problem with the mitochondria," says study co-author Jeffrey
Rothstein, M.D., Ph.D., professor of neurology and director of the Robert
Packard Center for ALS Research at Johns Hopkins.
The discovery provides new avenues to try to prevent or treat the
progressive, fatal condition, say the researchers, and creates the
possibility that mitochondria also might be involved in the more common
forms of ALS or in other neurodegenerative diseases.
Inherited ALS, which accounts for less than 5 percent of ALS cases, is
caused by a number of different mutations in the gene for superoxide
dismutase, or SOD1, an enzyme that normally helps clean toxic molecules from
cells. Each group of mice and rats studied by the researchers had been
engineered to carry one of these mutations. By studying whole mitochondria
purified from the brain, spinal cord and other tissues from the mice and
rats, and a variety of samples taken from an ALS patient at autopsy, the
researchers discovered that the outer mitochondrial surface was clogged with
mutant SOD1 protein in spinal cord nerve cells but not in other tissues.
"In essence, the proteins literally gum up the works," says the study's
leader, Don Cleveland, Ph.D., a scientist at UCSD and a researcher in the
Packard Center.
The researchers suggest that the "works" for mitochondria in
muscle-controlling nerves might be different from that in other cells. That
uniqueness could explain why only the motor neurons' mitochondria are
damaged and only those cells die, even though every cell in a rat, mouse or
person with inherited ALS carries the instructions for the mutant SOD1.
"We're viewing mitochondrial involvement as the greatest insult to the
spinal cord cells in this form of ALS," Cleveland says. "We believe it's
what pushes them over the edge."
The damaged mitochondria cause many problems and push the cell irreversibly
toward death. "We've long known, for example, that having abnormal
mitochondria makes neurons susceptible to injury from an excess of the
chemical transmitter glutamate," says Rothstein, who notes that glutamate
toxicity is a well-recognized aspect of ALS.
The scientists are beginning to test the potential role of mitochondrial
involvement in the more common, sporadic forms of ALS and to try to target
cell death and toxicity that stem from mitochondrial damage.
The study was funded by the U.S. National Institutes of Health, the Packard
Center for ALS Research at Johns Hopkins, the Spinal Cord Foundation, the
Bjorklund Foundation for ALS Research and the Paralyzed Veterans of America
Spinal Cord Research Foundation.
Authors on this paper are Cleveland, Jian Liu, Concepcion Lillo, Christine
Velde, Christopher Ward, Timothy Miller and David Williams of UCSD;
Rothstein, Jamuna Subramaniam and Philip Wong of Johns Hopkins (Wong is also
with the Packard Center); P. Andreas Jonsson, Peter Andersen, Stefan
Marklund and Thomas Brannstrom at Umea University in Sweden; and Ole Gredal
of the Bispebjerg Hospital in Copenhagen, Denmark.