The proteins that have now been identified shouldn't actually exist. Nevertheless, they build the core of cellular aggregates whose identity has been enigmatic until now. These aggregates are typically associated with hereditary neurodegenerative diseases including variants of frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). They are likely to be damaging and might be a target for therapy.
FTD and ALS are part of a group of neurodegenerative diseases that show a broad and overlapping variety of symptoms: Patients often suffer from dementia, personality changes and may also be affected by language abnormalities and movement disorders. The problems often arise before the age of 65 without a clear cause. However, about 30 percent of cases are linked to a genetic cause. In Europe approximately 10 percent of patients show a common genetic feature: In their DNA (the carrier of the genetic code) a particular short sequence appears in numerous copies one after another. Furthermore, proteins of unknown identity accumulate inside the brain of these patients. As it turns out both findings are directly related – that is what the team of researchers including molecular biologists Dieter Edbauer and Christian Haass has now been able to show.
"We have found that the proteins are linked to a genetic peculiarity which many patients have in common. At a certain location inside the gene C9orf72 there are several hundred repeats of the sequence GGGGCC, while healthy people display less than 20 such copies," explains Prof. Edbauer, who researches at the DZNE and the LMU. "But it is surprising that these proteins are actually made, because these repeats fall into a region of the DNA that should not be translated into proteins."
An area of DNA assumed to be silent
The DNA holds the blueprints for building proteins. In general, the beginning of such a blueprint is indicated by a certain molecular start signal, but the usual signal is missing in this case. The region of DNA comprising the numerous repeats should therefore not be translated into proteins. It seems that the process of protein synthesis is initiated in a non-textbook way. "Although quite rare there are two known alternatives to the common mechanism. Which procedure applies here, we don't know yet," says Prof. Haass, Site Speaker of the DZNE in Munich and chair of Metabolic Biochemistry at LMU.
Nevertheless, in cell culture experiments the researchers were able to show that long repeats of the sequence GGGGCC may in fact lead to the production of proteins, even though the usual start signal is missing. Furthermore, they identified the same proteins in the particles that typically accumulate in the brain of patients. The scientist could also identify their composition: They turned out to be dipeptid-repeat proteins, which comprise a very large number of identical building blocks.
"These are very extraordinary proteins that usually don't show-up in the organism," Edbauer notes. "As far as we know, they are completely useless and scarcely soluble. Therefore, they tend to aggregate and seem to damage the nerve cells. We haven't formally proven toxicity, but there is ample evidence." Because of their peculiarity these proteins might be an interesting target for new therapies. "As the mechanism of their production is so unusual, we may find ways to inhibit their synthesis without interfering with the formation of other proteins. One could also try to block their aggregation and accelerate their decomposition."
The scientists have applied for a patent and are pursuing a major goal. "At the DZNE in Munich it is our dream to develop a therapy against these devastating diseases," Haass and Edbauer conclude.
„The C9orf72 GGGGCC Repeat is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS", Kohji Mori, Shih-Ming Weng, Thomas Arzberger, Stephanie May, Kristin Rentzsch, Elisabeth Kremmer, Bettina Schmid, Hans A. Kretzschmar, Marc Cruts, Christine Van Broeckhoven, Christian Haass, Dieter Edbauer, Science Express, doi: 10.1126/science.1232927.
Helmholtz Association of German Research Centres: http://www.helmholtz.de/en/index.html
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
Claims that Ai Hin was faking pregnancy to get better treatment have been debunked by leading panda expert
The recent release of Susan Greenfields new book and the film Lucy, both of which are dependent on tired misconceptions or dubious theories about the brain, suggest one worrying conclusion: we are running out of myths about the brain. So here are some new ones, to keep things mysterious
These are the siphonophores, some 180 known species of gelatinous strings that can grow to 100 feet long, making them some of the longest critters on the planet. But instead of growing as a single body like virtually every other animal, siphonophores clone themselves thousands of times over into half a dozen different types of specialized cloned bodies, all strung together to work as a team---a very deadly team at that.
Researchers who study memory have had a thrilling couple of years. Some have erased memories in people with electroshock therapy, for example. Others have figured out, in mice, how to create false memories and even turn bad memories into good ones.
Hunting bats don't just listen out for male frogs' mating calls: they can also use echolocation to detect when the frogs inflate their throat sacs
A crèche of 30 dinosaur infants looked over by an older animal shows that even terrible lizards needed a night away from the kids
Families have identifiable collections of microbes that travel with them. It can take just 24 hours for the microbes to take over a new house
When rabbits were domesticated, around 100 regions of their genome changed to make them less fearful, but the variations are not fixed
Scientists never understood what became of the Paleo-Eskimos who once peopled the north. Now they know—and there's new reason to miss them
NOAA whittles down initial list of 66 species to be covered by Endangered Species Act