Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

'Sticky' mice lead to discovery of new cause of neurodegenerative disease

15.08.2006
When a faulty protein wreaks havoc in cells and causes disease, researchers are usually quick to point the finger at a wayward gene. Now scientists are learning that some neurodegenerative diseases can develop even though a gene is perfectly normal. The diseases can be caused when the genetic instructions contained in the gene are not executed properly, leading to a lethal buildup of malformed proteins in brain cells.

The new studies by Howard Hughes Medical Institute (HHMI) investigator Susan L. Ackerman and colleagues at The Jackson Laboratory point to a novel mechanism behind the buildup of the toxic sludge that accumulates in neurons. Researchers have long known that neurodegenerative disorders can be caused by the gradual yet persistent accumulation of misfolded proteins in neurons that eventually triggers cell death. But this new mechanism points to errors in executing the genetic instructions, which are distinct from known causes of neurodegenerative diseases, such as Alzheimer's and Huntington's diseases.

HHMI investigator Susan L. Ackerman and her colleagues reported their findings in an August 13, 2006, advance online publication of the journal Nature. Ackerman's group collaborated on the studies with co-author Paul Schimmel at The Scripps Research Institute.

The researchers made their discovery by studying mice with a mutation called sticky (sti). Although named for the sticky appearance of their fur, the mice harbor much more serious problems beneath their unkempt coats: poor muscle control, or ataxia, due to death of Purkinje cells in a region of the brain called the cerebellum.

No one knew why Purkinje cells were dying in sticky mutant mice. To find out, Ackerman and her colleagues searched for the gene that was disrupted by the sti mutation. They were surprised to find a subtle defect in a gene that codes for part of the cell's protein synthesis machinery -- an enzyme called alanyl tRNA synthetase. This enzyme is responsible for loading, or "charging" the amino acid alanine onto transfer RNAs (tRNAs). Transfer RNAs transport individual amino acids to the cell's protein synthesis machinery, where they are added to the growing stringlike protein molecules being manufactured there. Each tRNA is designed to carry only one of the 20 amino acids used to build proteins, and accurate loading is critical for the resulting protein to have the correct structure.

Ackerman said that when the team began its studies, it did not expect that such a fundamental defect in protein synthesis could be behind the neurodegeneration they had observed in sticky mice. "There were a lot of candidate genes in the chromosomal region containing the sti mutation," she said, "and this gene was actually the last candidate gene we investigated. It seemed to us that a mutation in a gene so fundamentally important for protein translation would cause early lethality. But when we couldn't find a defect in any of the other genes in the sti region, we decided to look closer at the tRNA synthetase gene. And there it was."

To set aside any doubts they might have had about the role of the tRNA synthetase gene, Ackerman and her colleagues showed that they could correct the pathology in the sticky mouse mutants by using genetic techniques to insert a normal version of the tRNA synthetase gene.

To understand the specific defect in the tRNA synthetase gene, Ackerman and her colleagues collaborated with Schimmel, whose research has concentrated on the biochemistry of synthetases. Molecular studies by Schimmel and his colleagues revealed that the defect in the sti mutant mouse occurred in a region of the synthetase enzyme that "edits" the loading of the correct amino acid, alanine, onto its carrier tRNA. This editing enables the enzyme to reject incorrect amino acids.

The researchers found that the mutant enzyme would charge an incorrect amino acid, serine, which resembles alanine, to tRNAs meant to carry only alanine. That meant that these tRNAs, said to be mischarged, would incorporate the incorrect amino acid into proteins. Although proteins begin as long strings of amino acids, they are ultimately folded into intricate three-dimensional shapes in order to function properly. Malformed proteins resulting from serine substitution could fold improperly, clogging and eventually killing cells.

When Ackerman and her colleagues examined the Purkinje cells of sticky mouse mutants, this is exactly what they saw. They also detected biochemical evidence that the cells were making an unsuccessful effort to tag and destroy the accumulating misfolded proteins.

"Our finding that this mechanism underlies a neurodegenerative disease was highly unexpected," said Ackerman. "It was perfectly obvious that mischarged tRNAs, may generate misfolded proteins. But what surprised us was that such a small increase in mischarged tRNAs could have such a devastating result in terms of neuronal survival. Nobody I know of has put forth such a mechanism for human neurological disease."

Ackerman speculates that human disease could arise when a mild inherited defect in a tRNA synthetase led to a subtle increase in malformed proteins, which could cause the death of particularly vulnerable cells such as Purkinje cells. "This mouse model shows that such a mechanism is possible," she said. "The sticky mouse has a mild editing defect that still allows it to produce offspring.

"So, a major question to be explored in human populations is whether the subtle loss of translational fidelity from such a defect could lead to various human diseases – particularly those that involve the accumulation of misfolded proteins," she said.

Ackerman and her colleagues are conducting further studies to understand why Purkinje cells are particularly vulnerable to defects in protein synthesis. They are also exploring how the actions of other genes in the cell can alleviate the pathology caused by protein misfolding.

Jennifer Michalowski | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Bolstering fat cells offers potential new leukemia treatment
17.10.2017 | McMaster University

nachricht Ocean atmosphere rife with microbes
17.10.2017 | King Abdullah University of Science & Technology (KAUST)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Ocean atmosphere rife with microbes

17.10.2017 | Life Sciences

Neutrons observe vitamin B6-dependent enzyme activity useful for drug development

17.10.2017 | Life Sciences

NASA finds newly formed tropical storm lan over open waters

17.10.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>