Researchers describe molecular 'two-step' leading to protein clumps of Huntington's disease

Mar 08, 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.

Source: University of Pittsburgh Schools of the Health Sciences

Explore further: Herpes virus hijackers

Related Stories

Protein aggregates save cells during aging

May 08, 2015

As an organism ages, a gradual loss of cellular protein quality control occurs. This results in the increased production of toxic protein clumps, so-called aggregates. Using a comprehensive approach, researchers ...

New 3-D method improves the study of proteins

Apr 27, 2015

Researchers have developed a new computational method called AGGRESCAN3D which will allow studying the 3D structure of folded globular proteins and substantially improve the prediction of any propensity for ...

Cells target giant protein crystals for degradation

Mar 12, 2015

Researchers at the RIKEN Brain Science Institute in Japan engineered a fluorescent protein that rapidly assembles into large crystals inside living cells, and showed that cells actively targeted the crystals ...

The super-resolution revolution

Feb 27, 2015

Cambridge scientists are part of a resolution revolution. Building powerful instruments that shatter the physical limits of optical microscopy, they are beginning to watch molecular processes as they happen, ...

Recommended for you

Herpes virus hijackers

May 22, 2015

The virus responsible for the common cold sore hijacks the machinery within our cells, causing them to break down and help shield the virus from our immune system, researchers from the University of Cambridge ...

Bacteria cooperate to repair damaged siblings

May 21, 2015

A University of Wyoming faculty member led a research team that discovered a certain type of soil bacteria can use their social behavior of outer membrane exchange (OME) to repair damaged cells and improve ...

New antibody insecticide targets malaria mosquito

May 20, 2015

Malaria is a cruel and disabling disease that targets victims of all ages. Even now, it is estimated to kill one child every minute. Recent progress in halting the spread of the disease has hinged on the ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.