Hidden in an intron of a gene with unknown function, a code of six nucleotides repeats ad infinitum. This constant GGGGCC refrain, near the coding region of the C9orf72 gene, is associated with the motor disease amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which causes dementia. But how such repeated nucleotides in an intron triggered neural disease remained unknown.
“What’s exciting about this family of proteins is that they’re completely artificial, in a way,” says study author Dieter Edbauer, a neuroscientist at the German Center for Neurodegenerative Diseases (DZNE) in Munich. “They are not present in healthy people at all [unlike amyloid-beta and tau], so we could probably safely get rid of all these proteins and not harm the person.”
Although the C9orf72 GGGGCC repeat has only recently been shown to play a role in ALS and FTLD, it is now considered the most common familial mutation in families with those diseases, present in about 10% of European cases. Healthy people have fewer than 25 of these repeats (usually more like 3-8), but people with the disease can have hundreds.
Until now, little data existed to explain this connection. So when Edbauer heard Laura Ranum give a talk describing how certain genes could be translated without a start codon, “I was immediately hooked,” he said. “I thought, this could be it, because if you translate this repeat sequence, you’d find that you’d get these very hydrophobic proteins that are bound to aggregate and could easily cause disease.”
So Edbauer’s team, along with members of Christian Haass’ lab at the same institute, developed antibodies to the short peptides formed from translating the GGGGCC repeat in all reading frames (glycine-alanine, and, to a lesser extent, glycine-proline and glycine-arginine). Eventually, the team found that most of the characteristic dot-like and star-shaped inclusions in diseased human cerebellum, hippocampus, and frontotemporal neocortex neurons contained the proteins.
Edbauer thinks that these proteins are hard to degrade and, therefore, gradually accumulate in the cytoplasm. “After a couple of decades, people accumulate enough of this stuff to get sick, is my guess,” he says, and his lab is currently trying to inhibit expression, toxicity, and aggregation of these proteins.
“I’m a physician, and, of course, my long-term goal is to treat patients,” says Edbauer. “I think in this case, the chances are better than for other diseases since healthy people don’t make any of these proteins.”
1. Mori, K., S.-M. Weng, T. Arzberger, S. May, K. Rentzsch, E. Kremmer, B. Schmid, H. A. Kretzschmar, M. Cruts, C. Van Broeckhoven, C. Haass, and D. Edbauer. 2013. The c9orf72 GGGGCC repeat is translated into aggregating Dipeptide-Repeat proteins in FTLD/ALS. Science (February).