The findings point the way to potential therapies and showcase an investigative strategy
Scientists at The Scripps Research Institute (TSRI) have discovered that a gene mutation linked to hereditary spastic paraplegia, a disabling neurological disorder, interferes with the normal breakdown of triglyceride fat molecules in the brain. The TSRI researchers found large droplets of triglycerides within the neurons of mice modeling the disease.
Courtesy of The Scripps Research Institute.
Professor Benjamin Cravatt is chair of the Department of Chemical Physiology at The Scripps Research Institute.
The findings, reported this week online ahead of print by the journal Proceedings of the National Academy of Sciences, point the way to potential therapies and showcase an investigative strategy that should be useful in determining the biochemical causes of other genetic illnesses. Scientists in recent decades have linked thousands of gene mutations to human diseases, yet many of the genes in question code for proteins of unknown function.
“We often need to understand the protein function that is disrupted by a gene mutation, if we’re going to understand the mechanistic basis for the disease and move towards developing a therapy, and that is what we’ve tried to do here,” said Benjamin F. Cravatt, professor and chair of TSRI’s Department of Chemical Physiology.
There is currently no treatment for hereditary spastic paraplegia (HSP), a set of genetic illnesses whose symptoms include muscle weakness and stiffness, and in some cases cognitive impairments. About 100,000 people worldwide live with HSP.
In the new study, Cravatt and members of his laboratory, including graduate student Jordon Inloes and postdoctoral fellow Ku-Lung Hsu, focused on DDHD2, an enzyme of unclear function whose gene is mutated in a subset of HSP cases. “These cases involving DDHD2 disruption feature cognitive defects as well as spasticity and muscle wasting, so they’re among the more devastating forms of this illness,” said Cravatt.
To start, the researchers created a mouse model of DDHD2-related HSP, in which a targeted deletion from the DDHD2 gene eliminated the expression of the DDHD2 protein. “These mice showed symptoms similar to those of HSP patients, including abnormal gait and lower performance on tests of movement and cognition,” said Inloes.
Prior research had suggested that the DDHD2 enzyme is expressed in the brain and is involved somehow in lipid metabolism. One study reported elevated levels of an unknown fat molecule in the brains of DDHD2-mutant HSP patients. Cravatt’s team compared the tissues of the no-DDHD2 mice to the tissues of mice with normal versions of the gene, and also found that the mutant mice had much higher levels of a type of fat molecule, principally in the brain.
Using a set of sophisticated “lipidomics” tests to analyze the accumulating fat molecules, they identified them as triglycerides—a major component of stored fat in the body, and a risk factor for obesity, atherosclerosis and type 2 diabetes.
“We were able to show as well, using both light microscopy and electron microscopy, that droplets of triglyceride-rich fat are present in the neurons of DDHD2-knockout mice, in several brain regions, but are not present in normal mice,” said Inloes.
For the next phase of the study, Cravatt’s team developed a complementary tool for studying DDHD2’s function: a specific inhibitor of the DDHD2 enzyme, one of a set of powerful enzyme-blocking compounds they had identified in a study reported last year. “After four days of treatment with this inhibitor, normal mice showed an increase in brain triglycerides,” said Inloes. “This suggests that DDHD2 normally breaks down triglycerides, and its inactivity allows triglycerides to build up.”
Finally the team confirmed DDHD2’s role in triglyceride metabolism by showing that triglycerides are rapidly broken down into smaller fatty acids in its presence.
“These findings give us some insight, at least, into the biochemical basis of the HSP syndrome,” said Cravatt.
Future projects in this line of inquiry, he adds, include a study of how triglyceride droplets in neurons lead to impairments of movement and cognition, and research on potential therapies to counter these effects, including the possible use of diacylglycerol transferase (DGAT) inhibitors, which reduce the natural production of triglycerides.
Cravatt also notes that the same approach used in this study can be applied to other enzymes in DDHD2’s class (serine hydrolases), whose dysfunctions cause human neurological disorders.
Other contributors to the study, “The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase,” were Melissa M. Dix, Andreu Viader, Kim Masuda, Thais Takei and Malcolm R. Wood, all of TSRI. Ku-Lung Hsu is now an assistant professor of chemistry at the University of Virginia.
Support for the study came from the National Institutes of Health (DA033760, DK099810, DA035864 and GM109315).
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation.
For more information, see www.scripps.edu
Madeline McCurry-Schmidt | newswise
A room with a view - or how cultural differences matter in room size perception
25.04.2017 | Max-Planck-Institut für biologische Kybernetik
Studying a catalyst for blood cancers
25.04.2017 | University of Miami Miller School of Medicine
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
25.04.2017 | Earth Sciences
25.04.2017 | Life Sciences
25.04.2017 | Earth Sciences