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.
The camel cousin evolved fluff instead of fat because it was able to linger in an evolutionary slow lane, suggest newly sequenced genomes
Archaeologists unearthed the missing head of one of the two sphinxes found guarding the entrance of an ancient tomb in Greece's northeast, as the diggers made their way into the monument's inner chambers, the culture ministry said on Tuesday.
In what the medical community is calling an incredible breakthrough, a Polish man who was left a quadriplegic after a stabbing, can walk again. The miraculous procedure involved doctors taking cells from his nose and implanting them into his spinal cord.
In a new book, San Francisco-based photographer Susan Middleton captures the curious gestures and expressions of marine invertebrates
Lab at the University of Texas at San Antonio gets Pentagon funding to see if brain waves can direct drone movement
After a severe brain injury, some people remain in a vegetative or minimally conscious state, unable to speak or move intentionally, and apparently unaware of the world around them. But in recent years, neuroscientists have found signs that some of these patients may still be conscious, at least to a degree. Now researchers have used a branch of mathematics called graph theory to search for neural signatures of consciousness.
Few parasitoids are more bizarre or disturbing than the wasps of the genus Glyptapanteles, whose females inject their eggs into living caterpillars. Once inside, the larvae mature, feeding on the caterpillar’s body fluids before gnawing through its skin en masse and emerging into the light of day. And despite the trauma, not only does the caterpillar survive---initially at least---but the larvae proceed to mind-control it, turning their host into a bodyguard that protects them as they spin their cocoons and finish maturing. Then, finally, the caterpillar starves to death, but only after the tiny wasps emerge from their cocoons and fly away.
From their new book A History of Life in 100 Fossils, Paul Taylor and Aaron O'Dea share the story of 10 incredible fossils
We love origin stories. When we see successful groups of animals and plants, we wonder where they came …
First research of its kind shows that tasers could impair a person's memory and thought process