For release: Thursday, February 29, 1996
For the first time, scientists have linked a critical cellular enzyme to the gene defect found in Huntington's and several other hereditary neurological diseases. The finding provides important clues about how these diseases may develop and suggests that a single therapy eventually may be developed to treat them.
The study is the first to examine how abnormally long chains of glutamine amino acids, produced by mutations linked to Huntington's disease and four other neurological disorders, interact with normal brain proteins. The work was funded by the Deane Laboratory at Duke University Medical Center, the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute on Aging. It appears in the March 1996 issue of Nature Medicine.*
Expanded glutamine chains, or polyglutamines, result from an abnormally large number of repeats of a normal three-base (trinucleotide) sequence in the genetic code - cytosine, adenine, and guanine, or CAG. Each CAG sequence codes for a single glutamine. Scientists believe long polyglutamines, which form part of a different protein in each CAG repeat disease identified so far, lead to progressive loss of specific groups of neurons. How this occurs, however, remains a mystery.
In the study reported this week, scientists led by Drs. Jeffery M. Vance and Warren J. Strittmatter at Duke University Medical Center in Durham, North Carolina, incubated long polyglutamine chains together with normal brain proteins. They found that one major protein, glyceraldehyde-3-phosphate dehydrogenase, or GAPDH, bound to a 60-glutamine peptide. This peptide represented the enlarged polyglutamines found in CAG repeat diseases. GAPDH also bound to two proteins with polyglutamine sequences: huntingtin (linked to Huntington's disease) and DRPLA protein (found in dentatorubral-pallidoluysian atrophy, another CAG repeat disease).
GAPDH's interaction with long polyglutamine chains "suggests that there might be a common mechanism in some, if not all, CAG repeat diseases," says Dr. James R. Burke, first author of the report. The findings also point to a potential strategy for treating these disorders, he says. CAG repeat diseases include Huntington's, DRPLA, spinocerebellar ataxias type 1 and 3, and X-linked spinobulbar muscular atrophy (Kennedy's disease).
Many genes normally contain chains of CAG repeats. People with fewer than 30 CAG repeats in a disease gene are generally unaffected, while those with more than 40 repeats usually develop disease. The number of repeats is unstable and can vary with each generation. People with longer CAG chains generally develop CAG repeat diseases at an earlier age and have more severe symptoms than people with shorter chains.
"GAPDH is an excellent candidate protein for involvement in the neurodegenerative process because of its many functions," the investigators say. Among its other roles, GAPDH is very important in glucose metabolism. Brain scans have shown that glucose breakdown is often impaired in neurodegenerative diseases long before neurons begin to die. "Over many years, subtle changes in neuronal metabolism may lead to death of vulnerable neurons," the scientists say. "Larger polyglutamine repeats are likely to have greater effects, consistent with the observation that patients with larger repeats generally develop disease at earlier ages."
GAPDH also acts in DNA repair, recognizing and removing any uracil nucleotides that are mistakenly added to DNA. Still other functions include binding to the cytoskeletal proteins actin and tubulin. Reduced activity of these proteins could be especially critical to long-lived cells like neurons, Burke suggests. Scientists must now determine which of GAPDH's many functions are important in CAG repeat diseases.
The reason each CAG repeat disease affects different neuron groups is still unclear. "Selective neuronal degradation cannot be explained solely by the cellular distribution of these proteins, since both the normal and mutant proteins in these diseases are widely expressed throughout the central nervous system," Strittmatter says in the report. However, cell-specific protein interactions or other factors may determine which cells die, he suggests.
GAPDH is found predominantly in the same parts of the cell - the cytoplasm, cytoskeleton, and membranes - as huntingtin and DRPLA proteins. This means interactions between GAPDH and these proteins are possible in living organisms.
GAPDH was recently linked to a third CAG repeat disease, spinocerebellar ataxia type 1, by Dr. Huda Zoghbi and colleagues at Baylor University in Houston, says Dr. Allen D. Roses. Roses directs the Deane Laboratory at Duke University, where the new study took place, and is an author on the report.
Many more variable-repeat genes have been identified but are not yet linked to a particular disease, Roses says in a commentary that appears in the same issue of Nature Medicine. Trinucleotide repeat mutations often vary in the number of repeats and may vary between identical twins, he notes, suggesting that these mutations may explain the variable susceptibility to schizophrenia and manic depressive disorder seen in twin studies.
"If these diseases have a common metabolic problem, such as inhibiting GAPDH activity, then developing drugs for uncommon neurodegenerative diseases may have a much larger potential application," Roses says. "Molecular genetic tools identify disease genes every week. The name of the game for the next decade is to discover relevant disease mechanisms."
While GAPDH is the main protein that bound long polyglutamines in this study, other proteins might be identified in the future, Vance says. Many conditions affect protein binding, both in culture and in the body, he explains. "This opens a whole new area to explore. It suggests that GAPDH may be a major player, but not an exclusive one."
The scientists are now studying GAPDH's interactions with other proteins to learn which of its functions might be disrupted. The brain is more dependent on glucose than most other organs, so a GAPDH-related change in metabolism might affect it specifically even though glucose is found throughout the body, Vance says. However, it is too early to confirm this idea. "This finding supplies a hypothesis and initial data that can now be tested," he says.
The NINDS, one of the National Institutes of Health located in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain.Originally prepared by Natalie Larsen, NINDS Office of Communications and Public Liaison.
Last Modified September 23, 2013