People who are afflicted with the rare neurodegenerative disorder spinocerebellar ataxia type 1 (SCA1) suffer damage to cerebellar Purkinje cells caused by a toxic buildup of the protein Ataxin-1. Researchers knew that SCA1, Huntington's disease and other related disorders arise because of a "genetic stutter," in which a mutation causes a particular gene sequence to repeat itself. These abnormal genetic repeats cause the resulting proteins to contain unusually long repetitive stretches of the amino acid glutamine.
The new findings, which are published in the August 26, 2005, issue of the journal Cell, provide a molecular explanation for Ataxin-1's assault on cerebellar Purkinje cells.
The findings should help to understand a range of diseases, including Huntington's disease, which are caused by an abnormal number of repetitive gene sequences. The discovery may also offer a new conceptual approach to understanding the pathology of Parkinson's disease and Alzheimer's disease, according to Huda Y. Zoghbi, a Howard Hughes Medical Institute investigator at the Baylor College of Medicine.
People with polyglutamine repeat disorders suffer severe degeneration in particular groups of neurons that vary depending on the type of disease. In SCA1, for example, the buildup of Ataxin-1 damages the cerebellar Purkinje cells. As a result of the damage, people with SCA1 lose balance and motor coordination. Loss of muscle control worsens until patients can no longer eat or breathe.
"We had known that the expansion of the glutamine tract within Ataxin-1 probably interfered with normal clearance of Ataxin-1,
Contact: Jim Keeley
Howard Hughes Medical Institute