|A Theme among Brain Diseases|
|'Stuttering' genes can lead to the loss of nerve cells in the brain and spinal cord|
|By Roberta Friedman
February 26, 2001
Huntington's disease belongs to a family of neurological disorders caused by genes that tend to expand. The expansion is a kind of stutter in the genome, a repeating stretch of DNA that runs on and on within a gene. The reasons a gene expands are not clear, but researchers know that prolonged repeats can lead to disease.
Short phrases of repetitive DNA that encode portions of proteins are common in genes. When the repeat expands, however, the extra DNA leads to malformed proteins that end up clogging brain cells, or neurons, with the cellular version of trash. Huntington's is the best known of the 'triplet-repeat' disorders (the repeated DNA sequence is 'CAG'), but stuttering genes also appear to underlie neurodegenerative diseases known as spinocerebellar ataxias.
The genomic mechanisms of DNA expansion may be fundamentally similar in these diseases. Studies published in recent months add to a growing body of literature on the common features of neurological disorders linked to stuttering genes, and in July researchers will compare notes and brainstorm ideas at a conference dedicated to triplet-repeat disorders.
These disorders have a common theme, says Stefan Pulst, Professor of Medicine at the University of California, Los Angeles, School of Medicine and head of neurology at Cedars-Sinai Medical Center. Most of the body's tissues can cope with malfunctioning components by making new cells, but in the brain, says Pulst, "you don't have that option." For a while, he explains, neurons may survive by putting the misshapen proteins in one corner of the cell, but "at some point the cell is stuck with the garbage it creates" and dies.
Pulst and colleagues have an animal model of the type-2 form of spinocerebellar ataxia. The researchers recreated the disease by inserting into mice the gene that is defective in humans, the ataxin-2 gene. The altered mice have damage to the brain cells that govern coordination and bear the brunt of injury in humans. And like humans, the mice showed the phenomenon of 'anticipation': an earlier onset and progression of symptoms seen among affected individuals in successive generations of the same family.
The CAG sequence common to these disorders codes for the amino acid glutamine. Normally, the repeating glutamine folds the protein properly. But in some families (for unknown reasons) the repeat goes on and onnot just ten or twenty times more but in some cases fifty or a hundred times. The abnormally shaped protein wreaks havoc within the cell.
"The repeats are normally there; what the mutation does is expand them," says Marie-Francoise Chesselet, of the Department of Neurology, the University of California, Los Angeles' School of Medicine. Chesselet is an organizer of the triplet-repeat meeting in July, which is supported by the Gordon Conference Foundation and will take place at Mount Holyoke College in Massachusetts.
Scientists propose that the repeats in the gene change the structure of the protein, such that it has a detrimental effect. Perhaps, says Chesselet, "it clogs the mechanism that normally degrades other proteins," or interacts with things that it doesn't normally contact, interfering with other molecules that are just trying to do their job.
Like Huntington's disease, most of the rarer ataxias are CAG-repeat disorders. But Pulst and his collaborators show that spinocerebellar ataxia type 10 reiterates a different sequence, a set of five bases. In this case, the repeat does not code for protein, and its function is a mystery. Pulst speculates that the expanded repeat may somehow interfere with the production of a protein.
Pulst's group also shows that the cellular debris in spinocerebellar ataxia type 2 need not accumulate in the cell's nucleus to cause damageit appears only in the surrounding cytoplasm. Other ataxias require a nuclear buildup to cause problems. This finding links at least one ataxia to more common diseases of aging such as Parkinson's and Alzheimer's. These diseases involve abnormal cytoplasmic deposits of tangled protein.
Researchers at the Gordon Conference will discuss similarities among the diseases' hallmark protein deposits. Scientists are seeking the commonalities among the disparate disorders, because, says Pulst, "for treatment trials, we need to know beforehand what we should lump together."
The field of CAG repeats has progressed far enough for researchers to begin high-throughput screening for therapeutics, says Chesselet. Some compounds seem to slow the disease in mice, at least for Huntington's. New models are being developed, says Chesselet, to allow companies to search without preconceived ideas for candidates that might not otherwise be identified with old-fashioned tactics of drug discovery.
In her work with mouse models, Chesselet is concentrating on the earliest stages of Huntington's disease. "Our focus is to understand exactly where and how it starts," she says. Damage to the brain, once incurred, is difficult to ameliorate. With the clearly genetic defects seen in the CAG-repeat disorders, there is an opportunity to screen for the gene and determine if an individual is at risk for the disease. Genetic screening could be key if and when viable therapies are developed.
See related GNN article
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