Huntington’s disease is caused by a renegade protein “huntingtin” that destroys neurons in areas of the brain concerned with the emotions, intellect and movement. All humans have the normal huntingtin protein, which is known to be essential to human life, although its true biological functions remain unclear.
Christopher Stanley, a Shull Fellow in the Neutron Scattering Science Division at ORNL, and Valerie Berthelier, a UT Graduate School of Medicine researcher who studies protein folding and misfolding in Huntington’s, have used a small-angle neutron scattering instrument, called Bio-SANS, at ORNL’s High Flux Isotope Reactor to explore the earliest aggregate species of the protein that are believed to be the most toxic.
Stanley and Berthelier, in research published today in Biophysical Journal, were able to determine the size and mass of the mutant protein structures¯from the earliest small, spherical precursor species composed of two (dimers) and three (trimers) peptides¯along the aggregation pathway to the development of the resulting, later-stage fibrils. They were also able to see inside the later-stage fibrils and determine their internal structure, which provides additional insight into how the peptides aggregate.
“Bio-SANS is a great instrument for taking time-resolved snapshots. You can look at how this stuff changes as a function of time and be able to catch the structures at the earliest of times,” Stanley said. “When you study several of these types of systems with different glutamines or different conditions, you begin to learn more and more about the nature of these aggregates and how they begin forming.”
Normal huntingtin contains a region of 10 to 20 glutamine amino acids in succession. However, the DNA of Huntington’s disease patients encodes for 37 or more glutamines, causing instability in huntingtin fragments that contain this abnormally long glutamine repeat. Consequentially, the mutant protein fragment cannot be degraded normally and instead forms deposits of fibrils in neurons.
Those deposits, or clumps, were originally seen as the cause of the devastation that ensues in the brain. More recently researchers think the clumping may actually be a kind of biological housecleaning, an attempt by the brain cells to clean out these toxic proteins from places where they are destructive. Stanley and Berthelier set out to learn through neutron scattering what the toxic proteins were and when and where they occurred.
At the HFIR Bio-SANS instrument, the neutron beam comes through a series of mirrors that focus it on the sample. The neutrons interact with the sample, providing data on its atomic structure, and then the neutrons scatter, to be picked up by a detector. From the data the detector sends of the scattering pattern, researchers can deduce at a scale of less than billionths of a meter the size and shape of the diseased, aggregating protein, at each time-step along its growth pathway.
SANS was able to distinguish the small peptide aggregates in the sample solution from the rapidly forming and growing larger aggregates that are simultaneously present. In separate experiments, they were able to monitor the disappearance of the single peptides, as well as the formation of the mature fibrils.
Now that they know the structures, the hope is to develop drugs that can counteract the toxic properties in the early stages, or dissuade them from taking the path to toxicity. “The next step would be, let’s take drug molecules and see how they can interact and affect these structures,” Stanley said.
For now, the researchers believes Bio-SANS will be useful in the further study of Huntington’s disease aggregates and applicable for the study of other protein aggregation processes, such as those involved in Alzheimer’s and Parkinson’s diseases.
“That is the future hope. Right now, we feel like we are making a positive contribution towards that goal,” Stanley said.
The research was supported by the National Institutes of Health. HFIR and Bio-SANS are supported by the DOE Office of Science.
ORNL is managed by UT-Battelle for the Department of Energy’s Office of Science.
NOTE TO EDITORS: You may read other press releases from Oak Ridge National Laboratory or learn more about the lab at http://www.ornl.gov/news. Additional information about ORNL is available at the sites below:
Twitter - http://twitter.com/oakridgelabnews
RSS Feeds - http://www.ornl.gov/ornlhome/rss_feeds.shtml
Flickr - http://www.flickr.com/photos/oakridgelab
YouTube - http://www.youtube.com/user/OakRidgeNationalLab
LinkedIn - http://www.linkedin.com/companies/oak-ridge-national-laboratory
Facebook - http://www.facebook.com/Oak.Ridge.National.Laboratory
Bill Cabage | Newswise Science News
Biologists unravel another mystery of what makes DNA go 'loopy'
16.03.2018 | Emory Health Sciences
Scientists map the portal to the cell's nucleus
16.03.2018 | Rockefeller University
Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...
On 15 March, the AWI research aeroplane Polar 5 will depart for Greenland. Concentrating on the furthest northeast region of the island, an international team...
The world’s second-largest ice shelf was the destination for a Polarstern expedition that ended in Punta Arenas, Chile on 14th March 2018. Oceanographers from...
At the 2018 ILA Berlin Air Show from April 25–29, the Fraunhofer Institute for Laser Technology ILT is showcasing extreme high-speed Laser Material Deposition (EHLA): A video documents how for metal components that are highly loaded, EHLA has already proved itself as an alternative to hard chrome plating, which is now allowed only under special conditions.
When the EU restricted the use of hexavalent chromium compounds to special applications requiring authorization, the move prompted a rethink in the surface...
At the ILA Berlin, hall 4, booth 202, Fraunhofer FHR will present two radar sensors for navigation support of drones. The sensors are valuable components in the implementation of autonomous flying drones: they function as obstacle detectors to prevent collisions. Radar sensors also operate reliably in restricted visibility, e.g. in foggy or dusty conditions. Due to their ability to measure distances with high precision, the radar sensors can also be used as altimeters when other sources of information such as barometers or GPS are not available or cannot operate optimally.
Drones play an increasingly important role in the area of logistics and services. Well-known logistic companies place great hope in these compact, aerial...
16.03.2018 | Event News
13.03.2018 | Event News
08.03.2018 | Event News
16.03.2018 | Earth Sciences
16.03.2018 | Physics and Astronomy
16.03.2018 | Life Sciences