LOS ANGELES -- Researchers at Cedars-Sinai Medical Center who have previously discovered and localized genes involved in neurodegenerative disorders called hereditary ataxias are presenting new findings about the underlying mechanisms causing these diseases.
Stefan-M. Pulst, M.D., Director of the Division of Neurology at Cedars-Sinai Medical Center who holds the Carmen and Louis Warschaw Chair in Neurology, was one of the lead scientists in the 1996 discovery of the spinocerebellar ataxia type 2 (SCA2) gene. His team was credited in early 1999 with identifying the chromosomal location of SCA10, a defective gene that is implicated in both ataxias and epilepsy.
The September issue of Nature Genetics will publish the results of a new study in which the scientists analyzed biologic, chemical and genetic mechanisms in an attempt to discover how mutation in the SCA2 gene actually causes damaged nerve cells. They studied SCA2 in cultured cells, human brains and transgenic mice, comparing their results with those of studies conducted on other genes within the same family of diseases.
The long-term goal of this research is to develop treatments for this specific disease and to discover any underlying mechanisms shared within the family of diseases, hoping that scientists will be able to interrupt the development of numerous neurological diseases.
Ataxia is an umbrella description of neurodegenerative disorders that cause such disabling symptoms as unsteadiness and an inability to coordinate muscle movements. More than 150,000 Americans suffer from ataxias.
Among this group of disorders is a subset of ataxias that are hereditary and caused by an abnormal number of "repeats" of a sequence in the genetic code: cytosine, adenine and guanine (CAG). In the case of SCA2, for example, the defective gene, found on chromosome 12, contains from 34 to 59 CAG repeats where there normally would be a string of 15 to 30. Researchers refer to this as an expansion of the polyglutamine (polyQ) tract, and the diseases are known as "triplet repeat diseases" or "CAG repeat diseases."
The other known CAG-repeat diseases are SCA1, Machado-Joseph disease (SCA3), SCA6, SCA7, Huntington disease, spinal bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. As the diseases are recognized and their genes discovered, scientists scrutinize the defective genes, the associated mutant proteins, and the underlying biologic and chemical mechanisms that may cause or allow defects and cell death to occur.
They compare such intricate, intracellular factors as whether fragments of genetic material appear to be clumped in the nucleus of nerve cells, whether genetic proteins are full-length or truncated, and the precise location where an "initial toxic event" occurs that leads to cell dysfunction and death.
In this study, scientists studied the pathogenesis of the SCA2 gene, looking at changes within the specific type of cell that is targeted by the mutant protein, ataxin-2, that causes the disease. This was made possible by generating a model of the disease in genetically engineered mice. According to the published article, the researchers identified several basic mechanisms within SCA2 cells that differ from those in other genes associated with neurodegenerative diseases.
The study demonstrates that while damage within the nucleus of cells is a factor in other cases, it is not necessary for all classes of polyQ-pathogenesis or for disease progression. Unlike some of the CAG-repeat diseases in which protein aggregation occurs in the nucleus, in SCA2 protein clusters in the cytoplasm, the material outside the nucleus. In this way, SCA2 is more similar to Parkinson's and Alzheimer's diseases, and the SCA2 animal model may be useful for the understanding to these diseases as well.
"Most human neurodegenerative diseases do not have a counterpart in the animal world." said Dr. Pulst. "Therefore, the creation of these diseases in animals using genetic engineering provides us the unique opportunity to study new treatments on animals before use in humans." In addition to his other responsibilities, Dr. Pulst directs Cedars-Sinai's Neurogenetics Laboratory, serves as scientific director of the Parkinson's Disease Research and Treatment Center at the medical center, and is a professor of medicine at the University of California, Los Angeles.
This research was supported by the Carmen and Louis Warschaw Chair for Neurology, F.R.I.E.N.D.s of Neurology, the National Ataxia Foundation, and a Long Term Disabled Scientist Supplement from the National Institutes of Health.
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Journal
Nature Genetics