Published online July 3 in Cell, their finding elucidates a previously unknown mechanism in human gene expression and opens the door for new therapeutic strategies against a thus-far untreatable neurological disease.
“This is the first example of a mechanism in a higher organism in which one gene creates two proteins from the same mRNA transcript, simultaneously,” said Christopher Gomez, MD, PHD, professor and chairman of the Department of Neurology at the University of Chicago, who led the study. “It represents a paradigm shift in our understanding of how genes ultimately encode proteins.”
The human genome contains a similar number of protein-coding genes as the nematode worm (roughly 20,000). This disparity between biological complexity and gene count partially can be explained by the fact that individual genes can encode multiple protein variants via the production of different sequences of messenger RNA (mRNA)—short, mass-produced copies of genetic code that guide the creation of myriad cellular machinery.
Gomez and his team, which included first author Xiaofei Du, MD, discovered a new layer of complexity in this process of gene expression as they studied spinocerebellar ataxia type-6 (SCA6), a neurodegenerative disease that causes patients to slowly lose coordination of their muscles and eventually their ability to speak and stand. Human genetic studies identified its cause as a mutation in CACNA1A—a gene that encodes a calcium channel protein important for nerve cell function—resulting in extra copies of the amino acid glutamine.
However, although the gene, mutation and dysfunction are known, attempts to find the biological mechanism of the disease proved inconclusive. Calcium channel proteins with the mutation still seemed to function normally.
Suspecting another factor at play, Gomez and his team instead focused on á1ACT, a poorly understood, free-floating fragment of the CACNA1A calcium channel protein known to express extra copies of glutamine in SCA6 cells. The researchers first looked at its origin and found that, to their surprise, á1ACT was generated from the same mRNA sequence as the CACNA1A calcium channel.
For the first time, they had evidence of a human gene that coded one strand of mRNA that coded two separate, structurally distinct proteins. This occurred due to the presence of a special sequence in the mRNA known as an internal ribosomal entry site (IRES). Normally found at the beginning of an mRNA sequence, this IRES site sat in the middle, creating a second location for ribosomes, the cellular machines that read mRNA, to begin the process of protein production.
Looking at function, Gomez and his team found that normal á1ACT acted as a transcription factor and enhanced the growth of specific brain cells. Importantly, mutated á1ACT appeared to be toxic to nerve cells in a petri dish, and caused SCA6-like symptoms in an animal model.
The team hopes to discover other examples of human genes with similar IRES sites to better understand the implications of this new class of “bifunctional” genes on our basic biology. For now, they are focused on leveraging their findings toward helping SCA6 patients and already are working on ways to silence mutated á1ACT.
“We discovered this genetic phenomenon in the pursuit of a disease cause and, in finding it, immediately have a potential strategy for developing preclinical tools to treat that disease,” Gomez said. “If we can target the IRES and inhibit production of this mutant form of á1ACT in SCA6, we may be able to stop the progression of the disease.”
This work was supported by the National Ataxia Foundation, the National Organization of Rare Diseases and the National Institute of Neurological Disorders and Stroke.
Kevin Jiang | Newswise
Transport of molecular motors into cilia
28.03.2017 | Aarhus University
Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside
The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.
To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
28.03.2017 | Life Sciences
28.03.2017 | Information Technology
28.03.2017 | Physics and Astronomy