The Parkin Protein and Disease Mutations

From the MRC Laboratory of Molecular Biology in the United Kingdom comes research that has determined the crystal structure of Parkin, a protein linked to Parkinson’s disease.  Results published in The EMBO Journal better define the positioning of many mutations that are linked to hereditary Parkinson’s disease.

Parkinson’s disease is a progressive neurodegenerative disease that occurs mostly in older individuals sporadically, or not hereditarily.  However, around 15% of patients develop symptoms early in life due to inherited mutations in a limited number of disease genes. These mutations are especially detrimental, causing more damage to nerve cells than non-mutated forms of Parkin.  Scientists believe this occurs because previous research has suggested the Parkin protein regulates energy production within cells.  For familial cases of inherited disease genes, around 50% are caused by mutations in the PARKIN gene that encodes a protein within the RBR ubiquitin ligase enzyme family. These mutated enzymes couple other proteins together within the cell to create a molecule called ubiquitin.  But since the enzymes catalyzing these reactions are mutated forms of the PARKIN gene, the critical ubiquitin proteins can be unstable or altered in their function.

EMBO investigator David Komander and his co-worker Tobias Wauer crystallized a form of human Parkin and used X-ray diffraction patterns to determine the way in which the protein chain folds into a three-dimensional structure. The experiments revealed the existence of an in-built control mechanism for Parkin activity, one that is lost in the presence of the mutations which cause Parkinson’s disease. Komander and Wauer pinpointed amino acids of Parkin that had key functions of ubiquitin ligase enzyme activity, and found that the proteins they create are sensitive to blocking by reagents that had already been categorized by their laboratory.  This means that after identifying building blocks of Parkin, the scientists blocked their ability to form larger, mutated, ubiquitin molecules.  The crystal structure of Parkin goes on to reveal secrets regarding the molecule, which scientists are hopeful may one day be used as a way to treat or slow the progression of Parkinson’s. There is reason to believe that other studies on crystal structure could lead scientists to find compounds that are capable of altering Parkin’s activity.

1) Tobias Wauer, David Komander. Structure of the human Parkin ligase domain in an autoinhibited state. The EMBO Journal, 2013; DOI: 10.1038/emboj.2013.125

2) EMBO – ecellence in life sciences (2013, May 31). How disease mutations affect the Parkin

protein. ScienceDaily. Retrieved June 3, 2013, from http://www.sciencedaily.com/releases/2013/05/

By: Lauren Horne

The Roskamp Institute is a 501(c)3 research facility dedicated to translating the efforts of its qualified research staff into real-world results for those suffering from neurological diseases. To learn more about our programs and to get information about donating, visit http://www.rfdn.org.

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Alzheimer’s disease: Molecular Trigger Found?

Scientists at Cambridge’s Department of Chemistry have been able to construct a detailed map that shows how the formation of aberrant proteins in the brain can lead to a build-up so massive that it causes the development of numerous brain-damaging diseases, chief among them being Alzheimer’s.

In 2010, the Alzheimer’s Research Trust found that dementia alone cost the UK economy 23 billion euros, more than the costs of cancer and heart disease combined. Normally, proteins are made up of chemical building blocks known as amino acids, which are joined together in a code ordered by our DNA. New proteins appear as long, thin strips, which are then intricately folded to properly carry out their designated biological function. However, there are points at which the amyloid-beta protein misfolds or unfolds and gets tangled with other newly-made proteins. The tangles stick to one another until they number in the millions, known as amyloid fibrils, and they start the huge deposits of proteins known as plaque, which are so large, they become insoluble.

When the plaque in the brain reaches a critical level, a chain reaction is set off, and new focal points of tendrils form. From these tendrils, a smaller number of proteins, known as toxic oligomers, can easily diffuse through membranes, effectively killing neurons and causing memory loss as well as other dementia symptoms. This new groundbreaking information required scientists to come together, using kinetic experiments with a framework of theory. Master equations, more commonly used in the fields of chemistry and physics, aided researchers in their efforts to better understand Alzheimer’s, and how effectively to fight it.

 

Sources:

 

Source 1)

University of Cambridge (2013, May 20). Molecular trigger for Alzheimer’s disease identified. ScienceDaily. Retrieved May 22, 2013,

 

Source 2)

Samuel I. A. Cohen, Sara Linse, Leila M. Luheshi, Erik Hellstrand, Duncan A. White, Luke Rajah, Daniel E. Otzen, Michele Vendruscolo, Christopher M. Dobson, and Tuomas P. J. Knowles. Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proceedings of the National Academy of Sciences, 2013; DOI: 10.1073/pnas.1218402110

 

By Lauren Horne

The Roskamp Institute is a 501(c)3 research facility dedicated to translating the efforts of its qualified research staff into real-world results for those suffering from neurological diseases. To learn more about our programs and to get information about donating, visit http://www.rfdn.org.