Researchers have recently discovered that an expansion of DNA in patients with the common neurodegenerative disorder Fragile X-associated Tremor syndrome causes the production of an abnormal protein that is toxic to neurons. The findings, which are reported online in the Cell Press journal Neuron, suggest an unexpected process by which DNA expansions might lead to neurodegenerative diseases - including Huntington's disease and ALS. This discovery reveals a common feature among these diseases that could be targeted to treat affected individuals.

The length of this particular DNA region is short and is not read, or translated, into a protein in normal individuals. "What we found surprised us - in cell culture models and in fly models of the human disease, the DNA expansion was in fact being translated into an aberrant protein that we call FMR1polyG," says first author Dr. Peter Todd, of the University of Michigan in Ann Arbor. "This protein was not translated in the same way as typical proteins, though. Rather, the expansion allowed protein translation to begin in the absence of a typical starting signal that's normally required for this process." This abnormal protein translation event, called "RAN" translation, occurs with different disease-causing DNA expansions to produce toxic proteins.

Importantly, RAN translation of the DNA expansions in affected patients and animals led to the accumulation of toxic FMR1polyG proteins in the brain. The investigators were able to suppress toxicity to neurons in fruit flies when they blocked production of the FMRpolyG protein. Conversely, toxicity to neurons was enhanced when they increased the protein's production.

"We were able to demonstrate that the ability to generate FMRpolyG was critical to elicit toxicity, suggesting that RAN translation is important in Fragile X-associated tremor ataxia syndrome and potentially other neurodegenerative disorders," says Dr. Todd.