Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Scripps Research Institute Scientists Shed Light on Cause of Spastic Paraplegia


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.

Uncovering Clues

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.

Looking Ahead

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

Madeline McCurry-Schmidt | newswise

More articles from Life Sciences:

nachricht Make way for the mini flying machines
21.03.2018 | American Chemical Society

nachricht New 4-D printer could reshape the world we live in
21.03.2018 | American Chemical Society

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Researchers at Fraunhofer monitor re-entry of Chinese space station Tiangong-1

In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.

Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...

Im Focus: Alliance „OLED Licht Forum“ – Key partner for OLED lighting solutions

Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.

They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...

Im Focus: Mars' oceans formed early, possibly aided by massive volcanic eruptions

Oceans formed before Tharsis and evolved together, shaping climate history of Mars

A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...

Im Focus: Tiny implants for cells are functional in vivo

For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.

In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...

Im Focus: Locomotion control with photopigments

Researchers from Göttingen University discover additional function of opsins

Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

International Tinnitus Conference of the Tinnitus Research Initiative in Regensburg

13.03.2018 | Event News

Latest News

TRAPPIST-1 planets provide clues to the nature of habitable worlds

21.03.2018 | Physics and Astronomy

The search for dark matter widens

21.03.2018 | Materials Sciences

Natural enemies reduce pesticide use

21.03.2018 | Life Sciences

Science & Research
Overview of more VideoLinks >>>