Malformed ion channels can be the cause of motor disorders. Scientists from Würzburg and Cambridge have now discovered how these channels manage to pass cellular quality control despite being folded abnormally. Their findings have refuted an old dogma.
Most people take activities like walking, running, jogging, but also breathing and swallowing for granted as processes that happen automatically in our body. But there are a number of diseases in which these processes are disturbed and can no longer take place automatically.
Professor Carmen Villmann, a Würzburg neurobiologist, is investigating the causes behind one of these disorders, the so-called "startle disease". She has recently identified mechanisms in the synthesis process of specific receptors as potential culprits. The Journal of Neuroscience has put this discovery on its front page.
"Allegedly simple processes such as walking or breathing are based on a number of signal processes and regulation and control mechanisms," Carmen Villmann explains. Environmental stimuli like touch or noise travel to the spinal cord and brainstem where they are processed. The muscles then receive the contraction frequency from the brain in a sequence that enables seemingly automatic movements and controls the breathing rhythm, for example.
Equilibrium between excitation and inhibition
"When signals are forwarded from the spinal cord to the muscles, excitation and inhibition processes have to be balanced in order to enable controlled movements," Villmann further. This process may be impaired by excessive excitation or missing inhibition. Such a motor disorder is also known as "startle disease" in medical lingo. The inhibitory signal transmission is impaired in persons affected by the disorder resulting in excessive excitation and stiffness of muscles.
"We have known for quite some time that glycine receptors in the spinal cord mediate this inhibition process," the neurobiologist explains. These receptor proteins form pores in the membrane of neurons and only allow negatively charged chloride ions to pass. Failure of such a receptor causes a disequilibrium between excitation and inhibition in favour of excitation and muscles get cramped as a result.
No all-or-none response in cells
The "startle disease" is hereditary and is caused by genetic defects. "Until recently, scientists believed a cellular all-or-none response to be responsible for the startle disease," Villmann states. This means that dominant mutations in the glycine receptors, which are nearly all located in the ion channel pore, were transported normally, but are associated with impaired channel conductivity because of their dominance. Due to their localisation inside the protein, recessive mutations cause the protein that is being synthesised to be folded abnormally; they are sorted out during synthesis. In collaboration with scientists from Cambridge, Carmen Villmann and her team have now asserted that this all-or-none assumption is not correct.
Before the cell can integrate a new receptor molecule into its membrane, this protein has to pass through several constituents of the cell during its synthesis process, similar to a product undergoing multiple processing steps on different machines. For example, the endoplasmic reticulum, the ER-Golgi intermediary compartment (ERGIC) and the secretory system of the different Golgi apparatuses are all involved in protein synthesis. If proteins are misfolded due to mutations, the quality control system in the endoplasmic reticulum prevents these proteins from travelling further.
Detailed insight into production processes
For their study the researchers first examined newly identified mutations of patients in cell culture systems. "We discovered that a small portion of the mutated receptors does in fact reach the cell membrane, but does not generate a functioning channel pore," Villmann says. Since such effects may also be triggered by the overproduction of proteins in artificial cell culture systems, the researchers subsequently investigated the mutated channel proteins in systems that result only in a low expression of the channel protein as well as in neurons.
"But the effects we observed were still the same: Subpopulations reach the cell membrane, but their number is too small to keep up the receptor's actual function," Villmann points out. A look into the cellular compartments allows each mutated channel protein to be tracked exactly: Some get as far as the Golgi apparatus and further on to the cell membrane, others only reach the ERGIC compartment and are found neither in the Golgi apparatus nor in the membrane.
This observation has led the research team to the following conclusion: "The mutation of a single of around 500 amino acids in the receptor does not necessarily have to result in the protein's massive misfolding which blocks the passage from the endoplasmic reticulum," Carmen Villmann explains. This interpretation is backed by the fact that all mutated receptors were marked by sugar molecules which is the prerequisite for being transported out of the endoplasmic reticulum.
There have to be other control mechanisms
Still, only a few mutated receptors manage to bypass the cellular quality checkpoints and reach the neuronal membrane, the final destination. "So there have to be additional control mechanisms in the subsequent compartments," Villmann assumes. Whether the proteins travel back to the endoplasmic reticulum or are directly singled out for degradation by compartments such as ERGIC and the Golgi apparatus remains yet to be answered. The group of Carmen Villmann aims to explore the depths of this cellular microcosm even further to study the signal pathways in this rare hereditary disease.
The research was funded by Deutsche Forschungsgemeinschaft DFG and by the EUproject Neurocypres.
"Disturbed neuronal ER-Golgi sorting of unassembled glycine receptors suggests altered subcellular processing is a cause of human hyperekplexia." Natascha Schaefer, Christoph J Kluck, Kerry L Price, Heike Meiselbach, Nadine Vornberger, Stephan Schwarzinger, Stephanie Hartmann, Georg Langlhofer, Solveig Schulz, Nadja Schlegel, Knut Brockmann, Bryan Lynch, Cord-Michael Becker, Sarah CR Lummis, and Carmen Villmann, J Neurosci. 2015 Jan 7;35(1):422-37. doi: 10.1523/JNEUROSCI.1509-14.2015.
Prof. Dr. Carmen Villmann, Institute of Clinical Neurobiology, Phone: +49 931 201-44035, firstname.lastname@example.org
http://www.neurobiologie.ukw.de/en/staff/prof-dr-c-villmann.html Carmen Villmann's Homepage
Gunnar Bartsch | Julius-Maximilians-Universität Würzburg
A 'half-hearted' solution to one-sided heart failure
24.11.2017 | Boston Children's Hospital
New study points the way to therapy for rare cancer that targets the young
22.11.2017 | Rockefeller University
High-precision measurement of the g-factor eleven times more precise than before / Results indicate a strong similarity between protons and antiprotons
The magnetic moment of an individual proton is inconceivably small, but can still be quantified. The basis for undertaking this measurement was laid over ten...
Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
24.11.2017 | Physics and Astronomy
24.11.2017 | Health and Medicine
24.11.2017 | Earth Sciences