Researchers identify proteins involved in new neurodegenerative syndrome

“They are two different diseases, but they are related to one gene,” said Dr. Juan Botas, associate professor of molecular and human genetics at BCM. Fragile X syndrome is the most common inherited form of mental retardation. It occurs in one in 4,000 males and one in 6,000 females.

The ways in which the two disorders occur differ. In both, the gene FMR1 contains too many repeats of the tri-nucleotide CGG. Those with fragile X syndrome have more than 200 repeats, causing the person to lack the fragile X mental retardation protein (FMRP) encoded by the gene. Those who develop fragile X-associated tremor/ataxia syndrome later in life have a “premutation” set of repeats of CGG totaling between 60 and 200. These individuals make the FMRP protein and do not develop fragile X syndrome. Previously, it was thought that 60-200 repeats had no effect on premutation carrier individuals. Now it appears that it does affect a subset of carriers, although it is unclear how many.

People with fragile X-associated tremors/ataxia syndrome suffer from tremor that becomes more severe over time. They have difficulty with walking and balance. Their disease can progress slowly over years until they have difficulty carrying out the activities of daily life. It is found in the grandfathers of children with fragile X syndrome, and it often begins when people are in the 50s and 60s. Most of those with the disease are men.

Researchers noticed that people with the fragile X-associated tremor/ataxia syndrome have higher than normal levels of messenger RNA. Messenger RNA or mRNA takes the protein’s blueprint from the DNA in the cell nucleus to the protein-manufacturing ribosome in the cytoplasm (the jelly-like material that fills the cell’s interior).

Studying fruit flies, Botas and his colleagues found two RNA-binding proteins hnRNP A2/B1 and CUGBP1 that are involved in the new disease. RNA-binding proteins control the metabolism of mRNA. However, these RNA-binding proteins tend to bind to CGG repeats. When there are too many CGG repeats, too many molecules of these proteins are bound to the repeats, preventing them from fulfilling their normal function of controlling mRNA metabolism.

When Botas and his colleagues created a fly with too many CGG repeats, the fly developed the neurodegenerative disease. However, when they developed a fly that made more than the normal amount of the RNA-binding proteins, the disease was much less severe.