Newly Discovered Genes Linked to Neurodegenerative Diseases

Death of a Neuron isn't on any best-seller list, but it continues to be one of the greatest mysteries in medical science, causing millions around the world to suffer from disorders such as Alzheimer's, Parkinson's and Huntington disease.

Although many genes are known to be responsible for these diseases, there is little understanding of how they cause neurons to degenerate and die. But scientists at Baylor College of Medicine are beginning to track down the molecular accomplices to these devastating disorders.

By studying the disease process from the time neuronal degeneration begins, a research team led by Dr. Juan Botas, a Baylor professor of molecular and human genetics and developmental biology, discovered certain genes that can modify the development of these diseases. Their findings were reported recently in the journal Nature.

Using the common fruit fly Drosophila, the researchers studied spinocerebellar ataxia type 1 or SCA1, a hereditary neurological disease caused by an error in the gene that codes for the protein known as ataxin-1.

SCA1 and related diseases are known as polyglutamine diseases because the resulting mutant protein has an unusually long polyglutamine tract. The mutant protein tends to clump inside the nucleus of the cell. According to Dr. Botas, neurons have difficulty recycling the mutant proteins.

"Because of previous work conducted at Baylor by Dr. Huda Zoghbi, we expected to find genes that are involved in protein folding and the destruction of abnormal proteins. And indeed, we saw neurons in the fly that went through all the pathogenic processes that characterize these neurons in human patients, including the formation of the protein clumps or aggregates, a hallmark of these diseases. These observations helped confirm those protein clearance mechanisms were taking place," Dr. Botas explained. "But we also found new genes involved in other pathways not previously known to be involved in neurodegenerative diseases," he said.

Among the new mechanisms implicated in SCA1 are genes involved in RNA processing, transcriptional regulation, and the detoxification of cells.

Now researchers must identify the corresponding genes in humans and determine how they contribute to the development of neurodegenerative diseases.

"The SCA1 Drosophila model provides new insight into the multi-faceted nature of SCA1 pathogenesis, opening new areas of research. A better understanding of these genes could lead to the development of drugs to slow or halt the degenerative process," Dr. Botas said.

Other Baylor researchers involved in the work are Dr. Zoghbi, a professor of pediatrics, molecular, and human genetics, neurology and neuroscience and a Howard Hughes Medical Institute investigator; and researchers in the laboratory of Dr. Botas, including Maria Capovilla, Pedro Fernandez-Funez, M. Laura Nino-Rosales, Beatrice de Gouyon, Wei-Chi She, James M. Luchak, Pedro Martinez, and Alanna McCall. Drs. Enrique Turiegano, Jonathan Benito and Inmaculada Canal with the Universidad Autonoma de Madrid also collaborated on the study as did Pamela J. Skinner and Dr. Harry T. Orr with the University of Minnesota.

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©2006 Texas Medical Center

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