Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scripps Research Institute Scientists Shed Light on Cause of Spastic Paraplegia

30.09.2014

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 www.scripps.edu

Madeline McCurry-Schmidt | newswise

More articles from Life Sciences:

nachricht Scientists enlist engineered protein to battle the MERS virus
22.05.2017 | University of Toronto

nachricht Insight into enzyme's 3-D structure could cut biofuel costs
19.05.2017 | DOE/Los Alamos National Laboratory

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

Im Focus: Using graphene to create quantum bits

In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.

In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...

Im Focus: Bacteria harness the lotus effect to protect themselves

Biofilms: Researchers find the causes of water-repelling properties

Dental plaque and the viscous brown slime in drainpipes are two familiar examples of bacterial biofilms. Removing such bacterial depositions from surfaces is...

Im Focus: Hydrogen Bonds Directly Detected for the First Time

For the first time, scientists have succeeded in studying the strength of hydrogen bonds in a single molecule using an atomic force microscope. Researchers from the University of Basel’s Swiss Nanoscience Institute network have reported the results in the journal Science Advances.

Hydrogen is the most common element in the universe and is an integral part of almost all organic compounds. Molecules and sections of macromolecules are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

Innovation 4.0: Shaping a humane fourth industrial revolution

17.05.2017 | Event News

Media accreditation opens for historic year at European Health Forum Gastein

16.05.2017 | Event News

 
Latest News

New approach to revolutionize the production of molecular hydrogen

22.05.2017 | Materials Sciences

Scientists enlist engineered protein to battle the MERS virus

22.05.2017 | Life Sciences

Experts explain origins of topographic relief on Earth, Mars and Titan

22.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>