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 Switch-in-a-cell electrifies life
18.12.2018 | Rice University

nachricht Plant biologists identify mechanism behind transition from insect to wind pollination
18.12.2018 | University of Toronto

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Data storage using individual molecules

Researchers from the University of Basel have reported a new method that allows the physical state of just a few atoms or molecules within a network to be controlled. It is based on the spontaneous self-organization of molecules into extensive networks with pores about one nanometer in size. In the journal ‘small’, the physicists reported on their investigations, which could be of particular importance for the development of new storage devices.

Around the world, researchers are attempting to shrink data storage devices to achieve as large a storage capacity in as small a space as possible. In almost...

Im Focus: Data use draining your battery? Tiny device to speed up memory while also saving power

The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.

Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

Im Focus: New Foldable Drone Flies through Narrow Holes in Rescue Missions

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

Pressure tuned magnetism paves the way for novel electronic devices

18.12.2018 | Materials Sciences

New type of low-energy nanolaser that shines in all directions

18.12.2018 | Physics and Astronomy

NASA research reveals Saturn is losing its rings at 'worst-case-scenario' rate

18.12.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>