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 Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

Im Focus: Bacterial Pac Man molecule snaps at sugar

Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.

The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

Water - as the underlying driver of the Earth’s carbon cycle

17.01.2017 | Earth Sciences

Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

17.01.2017 | Materials Sciences

Smart homes will “LISTEN” to your voice

17.01.2017 | Architecture and Construction

VideoLinks
B2B-VideoLinks
More VideoLinks >>>