Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study points to disruption of copper regulation as key to prion diseases

20.04.2009
An investigation of a rare, inherited form of Creutzfeldt-Jakob disease suggests that disrupted regulation of copper ions in the brain may be a key factor in this and other prion diseases.

Researchers at the University of California, Santa Cruz, discovered a striking relationship between changes in the copper-binding properties of abnormal prion proteins and the clinical features of prion disease in patients with certain rare, genetic mutations. They described their findings in a paper published by PLoS Pathogens on April 17.

"The loss of copper regulation may play a very important role in prion disease progression," said Glenn Millhauser, professor of chemistry and biochemistry at UCSC and corresponding author of the paper.

Prion diseases are fatal neurodegenerative brain disorders caused by a misfolded form of the normal cellular prion protein. Human prion diseases include classic and variant types of Creutzfeldt-Jakob disease (CJD). The vast majority of CJD cases are sporadic, meaning they are thought to arise from spontaneous misfolding of the prion protein. Infectious transmission of the prion accounts for a very small percentage of cases, while about 10 percent of cases are caused by inherited defects in the structure of the prion protein.

Millhauser and his coauthors studied the effects of insertional mutations that cause extra sequences of eight amino acids (known as the octarepeat sequence) to be incorporated into the prion protein. Whereas the normal prion protein has four octarepeat segments, insertional mutations can result in as many as nine additional octarepeats. The extra octarepeats change the properties of the prion protein and eventually lead to the progressive brain damage characteristic of CJD.

These insertional mutations are known from a small number of cases reported in the literature, involving about 30 families and 108 individuals. Reviews of these cases have suggested that higher numbers of inserts are associated with earlier-age onset of the disease.

The octarepeat domain takes up copper ions, which are essential for the proper functioning of neurons. Millhauser's lab looked at the effects of insertional mutations on the prion protein's ability to bind copper. Graduate student Daniel Stevens, lead author of the paper, and postdoctoral researcher Eric Walter performed experiments using magnetic resonance spectroscopy to study how prion proteins with different numbers of octarepeats interact with copper.

The normal prion protein responds dynamically to varying concentrations of copper by changing the way it binds the metal, allowing it to soak up more copper ions at higher concentrations. When the researchers studied proteins with octarepeat inserts, however, they found that the protein loses this ability to switch binding modes as the number of inserts increases beyond four.

"We got excited when we saw that the threshold in the effects on copper binding corresponds to the threshold for age of onset that was seen in the clinical studies," Millhauser said.

The average age of onset is 64 years for patients with one to four extra repeats, but for patients with five to nine inserts the average age of onset drops to 38 years. Similarly, Millhauser's group found a transition in the copper-binding properties of the protein that occurred between four and five inserts, the same threshold observed for early-onset disease.

For the statistical analysis of clinical cases, Millhauser enlisted the help of statisticians David Draper and Abel Rodriguez, professors of applied mathematics and statistics in the Jack Baskin School of Engineering at UCSC. Draper and Rodriguez used several approaches to analyze the pooled data from case studies in the literature. Their results are consistent with the existence of two groups of patients: a group with one to four extra octarepeats and late-onset disease, and a group with five or more inserts and early-onset disease.

The normal function of the prion protein remains uncertain, but the new findings support the idea that it plays a role in the regulation of copper ions in the brain, Millhauser said. The prion protein is anchored to the outside of the cell membranes of neurons and is concentrated at the synapses, the junctions between neurons where signals are transmitted. The concentration of copper in the synapses is dynamic, and as the copper concentration goes up and down the prion protein switches from one copper-binding mode to another. Millhauser suspects that the prion protein soaks up excess copper ions to protect brain cells from harmful reactions.

"The prion protein goes into a neuroprotective mode at higher levels of copper, and that mode gets lost when extra octarepeats are added to the protein structure," he said.

While changes in copper binding begin to appear with four or more extra octarepeats, other changes in the molecular properties of the prion protein occur with as few as one insert. These changes include an increased propensity to clump together and form protein deposits in brain tissue.

Research on prion diseases has tended to focus on these aggregates and deposits, which are thought to have toxic effects on brain cells. But the strong relationship between changes in copper binding and clinical progression of the disease suggests that more attention should be given to the normal function of the prion protein, Millhauser said.

"The fundamental issue may be the loss of copper regulation, and excess copper may be what causes the cytotoxicity," he said.

In addition to Millhauser, Stevens, Walter, Rodriguez, and Draper, the coauthors of the PLoS Pathogens paper include Paul Davies and David Brown of the University of Bath.

Tim Stephens | EurekAlert!
Further information:
http://www.ucsc.edu

More articles from Studies and Analyses:

nachricht New study from the University of Halle: How climate change alters plant growth
12.01.2018 | Martin-Luther-Universität Halle-Wittenberg

nachricht Disarray in the brain
18.12.2017 | Universität zu Lübeck

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

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

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Let the good tubes roll

19.01.2018 | Materials Sciences

How cancer metastasis happens: Researchers reveal a key mechanism

19.01.2018 | Health and Medicine

Meteoritic stardust unlocks timing of supernova dust formation

19.01.2018 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>