Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Pitt researchers describe molecular '2-step' leading to protein clumps of Huntington's disease

10.03.2009
In a paper published in the early online version of Nature Structural and Molecular Biology, researchers at the University of Pittsburgh School of Medicine deconstruct the first steps in an intricate molecular dance that might lead to the formation of pathogenic protein clumps in Huntington's disease, and possibly other movement-related neurological disorders.

Huntington's is one of 10 diseases in which a certain protein, different for each disease, contains polyglutamine, a stretch of repeating blocks of the amino acid glutamine, explained Ronald Wetzel, Ph.D., professor in the Department of Structural Biology and member of the Pittsburgh Institute for Neurodegenerative Diseases at the University of Pittsburgh School of Medicine. The affected protein in Huntington's disease is called huntingtin.

Most people have a huntingtin protein whose polyglutamine segment contains 20 or so glutamines, and even a polyglutamine with as many as 35 repeats may not cause Huntington's symptoms. But the risk of developing Huntington's disease rises sharply in individuals whose polyglutamine sequences are only slightly larger. A block of 40 repeats, for example, is associated with a very high likelihood of having the disease.

"To a protein chemist, this is a fascinating situation," Dr. Wetzel said. "Polyglutamine doesn't seem to play a sophisticated role in these proteins, and it doesn't have a defined structure. Yet by changing its length to only a very slight extent, it takes on some new physical properties that somehow initiate diseases."

One consequence of the lengthening is protein aggregation, or clumping, a feature that consistently appears in brain cells of patients who have one of these neurodegenerative diseases. Many research groups, including Dr. Wetzel's, study how polyglutamine expansion alters the huntingtin protein's behavior.

In its most recent studies, the Pitt team worked out the details of how the aggregation behavior of huntingtin depends, in a surprisingly intricate way, on the neighboring segments of amino acid sequence flanking the polyglutamine.

They found that longer polyglutamine sequences have the ability to disrupt the structure of a neighboring region, 17 amino acids long, at the beginning of the protein known as the N-terminus. That sets the stage for new physical interactions with the rest of the huntingtin protein that drive it to aggregate.

"If the N-terminus is not there, huntingtin makes clumps very slowly, even if the polyglutamine stretch is rather long," Dr. Wetzel noted. "When the N-terminus is disrupted by its polyglutamine neighbor, it takes a lead role in the aggregation process, with the polyglutamine then following to consolidate and stabilize the clumps – a kind of 'aggregation two-step'."

The choreography might be similar in other polyglutamine diseases, meaning physical disruption of neighboring regions may influence the tendency for the protein to clump, he added. More research is needed to establish whether the aggregates cause disease or are merely a marker for it, and to try to develop treatments that can redirect the protein dance or perhaps halt it entirely. "For those of us interested in developing therapeutics," Dr. Wetzel notes, "the strong role played by the N-terminus in initiating aggregation gives us another possible molecular target."

Huntington's disease is an inherited disease in which progressive degeneration of certain brain neurons causes uncontrolled writhing, twisting and jerking movements, and cognitive and psychiatric problems. It was once called Huntington's "chorea", from a Greek word for dance.

Anita Srikameswaran | EurekAlert!
Further information:
http://www.upmc.edu

More articles from Life Sciences:

nachricht Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University

nachricht How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

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...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>