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STUDY SINGLES OUT MITOCHONDRIAL DAMAGE AS KEY PROBLEM IN ALS Packard Center and other scientists discover why motor neurons are targeted in animal models, a patient with the inherited form of the disease. The work suggests new therapeutic approaches. Amyotrophic lateral sclerosis (ALS) almost exclusively targets motor neurons in the spinal cord and parts of the brain. That’s true for the common form of the illness that strikes from nowhere, as well as for the rarer inherited type, where every body cell is capable of producing an abnormal protein, thanks to a mutated gene. But nobody knows why. Now researchers with the Robert Packard Center for ALS Research at Johns Hopkins and with the University of California, San Diego, have taken a major step in explaining why specific neurons are singled out. Their studies in both rat and mouse models of ALS and in a human patient with an inherited form of the disease point to abnormal goings-on in the mitochondria of affected cells. Mitochondria are the small bodies within cells that produce energy to sustain life. Basically, the scientists say, flawed proteins that appear in nerve cells are drawn to the mitochondrial surface where they interfere with a system mitochondria use to import needed substances. “The proteins literally ‘gum up the works,’” says the Packard center’s Don Cleveland, Ph.D., the lead researcher and a scientist at UCSD. The reason mitochondria in brain and spinal cord cells are singled out, Cleveland suggests, is likely because of an as-yet undiscovered specialization those cells have in their mitochondrial import mechanism. An account of the work appears this week in the journal Neuron. The study also shows that damage to mitochondria in ALS animal models not only mimics the course of human disease, but that it’s what sets cells on their last downhill path, triggering apoptosis, the series of “cell suicide” reactions normally used to remove damaged or unnecessary cells. “We’ve long known mitochondria look abnormal in motor neurons of model animals and in ALS patients with either sporadic or familial forms of the disease,” Cleveland explains. “Also, other neurodegenerative diseases arise from specific mitochondrial damage. Hereditary spastic paraplegia and Friedreich ataxia, for example, result from specific injury to mitochondria. Like ALS, both diseases cause neuron death and subsequent muscle weakness.” “But this is the first time that any one has shown a tie between ALS and the upset of a natural process that takes place in mitochondria. It’s also the first study to show why the damage is specific to spinal cord mitochondria,” says Johns Hopkins co-researcher Jeffrey Rothstein, M.D., Ph.D., who also directs the Packard Center. In their studies, the researchers carefully purified whole mitochondria from a variety of tissues in animal models and from an ALS patient at autopsy. Different parts of the brain, the spinal cord, liver and skeletal muscle were sources of mitochondria. The scientists used subgroups of transgenic rodents, each carrying a specific human mutation to mirror one found in patients with an inherited form of ALS. The various mutations strike the human SOD1 gene which codes for the superoxide dismutase enzyme. In normal cells, that enzyme typically appears in a cell’s cytoplasm and has a detoxifying effect. The researchers discovered that in spinal cord neurons of animal models—and in the patient—the outer mitochondrial surface is “clogged” with mutant SOD1 protein. This doesn’t happen in the animals’ other tissues. Nor does it occur in control rodents with normal genes, which, of course, have nothing unusual about their mitochondria. Also, with some of the SOD1 mutations, the resulting flawed protein appears able to get inside mitochondria, where it can’t behave like a normal enzyme and likely disrupts normal mitochondrial activity. It’s like starting a flawed engine and having it catch the car on fire, leaving it behind as a useless, twisted mass. Injured mitochondria further alter a cell’s chemistry, pushing 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 nerve transmitter, glutamate,” says Rothstein. “ And glutamate toxicity is a well-recognized aspect of ALS.” Injured mitochondria also signal the onset of apoptosis in cells. “We’re viewing mitochondrial involvement as the greatest insult to the spinal cord cells,” Cleveland adds. “We believe it’s what pushes them over the edge.” Finally, says Cleveland, the process in mitochondria parallels what scientists observe in a number of the animal models. It begins gradually before signs of cell damage appear under the microscope and before animals sicken. Pathology doesn’t surface in young animals. Once it’s in full swing, however, the animals quickly and dramatically become ill. These findings, however, will prove useful, the researchers say. Identifying mitochondria as a primary target for ALS offers new approaches for therapy. The most likely ones being explored by Packard Center scientists aim to suppress the suicide and the glutamate-toxicity pathways as they’re inappropriately triggered. Researchers have singled out several vulnerable points on those paths and are testing ways to block them. Other researchers in this study are Jian Liu, Concepcion Lillo, Christine Velde, Christopher Ward, Timothy Miller and David Williams of UCSD, and Jamuna Subramaniam and Philip Wong of Johns Hopkins. (Wong is also a researcher with the Packard Center.) P. Andreas Jonsson, Peter Andersen, Stefan Marklund, Thomas Brännström at Ümea University in Sweden were on the research team, as was Ole Gredal, with the Bispebjerg Hospital in Copenhagen, Denmark. The study was funded by NIH grants, by the Packard Center for ALS Research
at Johns Hopkins, by funding from the Spinal Cord Foundation and the Bjorklund
Foundation for ALS Research as well as the Paralyzed Veterans of America
Spinal Cord Research Foundation. |
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