Huntington proteins and their nasty 'social network'

Feb 27, 2014

Researchers at the Buck Institute have identified and categorized thousands of protein interactions involving huntingtin, the protein responsible for Huntington's disease (HD). To use an analogy of a human social network, the identified proteins are like "friends" and "friends of friends" of the HD protein. The network provides an invaluable resource for identifying targets to treat the disease and has been used to implicate a particular signaling pathway involved in cell motility. HD is an incurable, fatal, inherited neurological disorder that causes severe degeneration of the nervous system.

The research appears in the March 7, 2014 edition of the Journal of Biological Chemistry and was chosen as the Paper of the Week. The Journal's editorial board members consider this study to be in the top 2% of those to be published this year in terms of significance and overall importance.

HD is caused by a mutation in the human HTT gene that results in an abnormal expansion and misfolding of the corresponding . Buck researchers established an unprecedented large-scale interaction network for the huntingtin protein identifying 2,141 highly interconnected proteins that have over 3,200 interactions among them.

The work involved a close collaboration between Buck faculty members Robert E. Hughes, PhD, an expert in neurodegeneration, and Sean D. Mooney, PhD, who leads the Institute's bioinformatics program. Researchers analyzed protein interaction data generated at Prolexys Pharmaceuticals that identified more than 100 huntingtin interacting proteins (HIPs) and more than 2,000 proteins that interact with HIPs. "The damage caused by the mutant huntingtin protein radiates out through the cell, like a pebble dropped in a pond. In this case, the pond is filled with proteins that make up much of the cell," said Hughes. "We now have a handle on the detailed structure of a complex web of interactions that causes global dysfunction in cells resulting in degeneration of the brain."

Hughes said Mooney employed sophisticated computational methods which allowed researchers to comprehensively analyze the functions or so-called "jobs" of the proteins and networks and how they might be impacted by the huntingtin mutation. The investigators identified several pathways that were particularly conspicuous in the network. In particular, HD mutations impacting the RhoGTPase signaling pathway interfered with filopodia, the slender projections that cells use to direct movement and communicate with other cells. The data indicate that the HD mutation directly affects membrane dynamics, cell attachment and . Defects in these pathways can provide critical clues for how to best intervene in the disease with drugs.

Highlighting the collaboration, Hughes said, "This study demonstrates how the synergy between experimental and computational approaches can help unravel the nature of a complex disease such as HD." Mooney added, "Understanding and characterizing potentially functional HD interactions gives scientists new tools to connect genomic, genetic, proteomic and other molecular changes to identify the causes of this deadly disease. Bioinformaticians can add this dataset to their systems biology toolbox in the quest for interventions that can suppress the progression of HD."

Explore further: Why plants don't get sunburn

More information: Journal of Biological Chemistry; Vol. 289, issue 10; PubMed PMID: 24407293.

add to favorites email to friend print save as pdf

Related Stories

Immune cell migration is impeded in Huntington's disease

Nov 19, 2012

Huntington disease (HD) is an incurable neurodegenerative disease caused by a mutation in the huntingtin gene (htt). Though most of the symptoms of HD are neurological, the mutant HTT protein is expressed in non-neural cells ...

Recommended for you

Why plants don't get sunburn

Oct 29, 2014

Plants rely on sunlight to make their food, but they also need protection from its harmful rays, just like humans do. Recently, scientists discovered a group of molecules in plants that shields them from ...

Viral switches share a shape

Oct 27, 2014

A hinge in the RNA genome of the virus that causes hepatitis C works like a switch that can be flipped to prevent it from replicating in infected cells. Scientists have discovered that this shape is shared by several other ...

'Sticky' ends start synthetic collagen growth

Oct 27, 2014

Rice University researchers have delivered a scientific one-two punch with a pair of papers that detail how synthetic collagen fibers self-assemble via their sticky ends.

Cell membranes self-assemble

Oct 27, 2014

A self-driven reaction can assemble phospholipid membranes like those that enclose cells, a team of chemists at the University of California, San Diego, reports in Angewandte Chemie.

Emergent behavior lets bubbles 'sense' environment

Oct 27, 2014

Tiny, soapy bubbles can reorganize their membranes to let material flow in and out in response to the surrounding environment, according to new work carried out in an international collaboration by biomedical ...

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.