University of Kassel: "Molecular switch" discovered in Parkinson's protein

After Alzheimer's, Parkinson's is the most common neurodegenerative disease; estimates put the number of sufferers at around seven million worldwide. Part of the disease is hereditary and is caused by mutations of certain genes. This so-called familial Parkinson's variant occurs with varying frequency in different ethnic groups; certain mutations are particularly common in Italy and Spain. Mutations of a protein called LRRK2 are thought to be the most common cause of hereditary Parkinson's.

A research group including scientists from the University of Kassel has now discovered a "molecular switch" that controls the activity of this protein. "Our findings may point to ways of developing drugs that regulate the activity of this protein and thus offer new approaches to treating hereditary Parkinson's disease," explains Prof. Dr. Friedrich W. Herberg, head of the Department of Biochemistry at the University of Kassel. "However, it may also be possible to derive approaches for the treatment of other Parkinson's variants from the results."

The protein LRRK2 is also called "Dardarin," from the Basque "dardara" meaning "to tremble." In the human cell, it has a mediating function because it supplies other proteins with phosphates. Dardarin plays a special role in certain cells of the midbrain that produce the neurotransmitter dopamine. In Parkinson's patients, these cells in the midbrain die; the resulting dopamine deficiency then leads to the familiar symptoms such as muscle tremors, or even depression and loss of the sense of smell.

The Kassel researchers have closely examined individual areas of the enzyme Dardarin. "Proteins are made up of building blocks called amino acids. We found that in Dardarin mutations, which are held responsible for hereditary Parkinson's, phosphate supply is disturbed in a region around amino acid 1441," describes Dipl. Biol. Kathrin Muda, one of the authors of a study that has now appeared in the journal Proceedings of the National Academy of Science. "Most importantly, we found out: Another, so-called 14-3-3 protein can bind in the 1441 region and thus influence the activity of Dardarin. In the mutant variant, binding to Dardarin is disrupted and Dardarin activity is no longer properly regulated." How this leads to the death of cells in the midbrain is not yet known. "If we can find a way to replace the binding with 14-3-3 for the mutant variant of dardarin with another mechanism that has the same effect, we will be a big step closer to drug development," Muda explains. 

In collaboration with scientists from the Universities of Tübingen, the Helmholtz Center in Munich and the Cancer Research Center in Heidelberg, the Kassel researchers used what is known as mass spectrometry, actually a method for weighing atoms and molecules, for their study. By comparing the weight of normal and mutant LRRK2 protein fragments, they were able to draw conclusions about phosphate supply.

The research group at the University of Kassel focuses on protein kinase A (PKA), an enzyme that is involved as a mediator in many processes in human cells, including phosphate supply to LRRK2. In addition to Herberg and Muda, the Kassel scientists Dr. Daniela Bertinetti and Dipl. Biol. Jennifer Sarah Hermann as well as Dr. Frank Gesellchen from Glasgow were involved. The Department of Biochemistry at the University of Kassel is involved in a consortium for research into human proteins(www.affinomics.org). The study was supported by the EU, the Otto-Braun-Fonds and the foundation of the actor Michael J. Fox, who suffers from Parkinson's disease.

Image by Dipl. Biol. Kathrin Muda (Photo: Uni Kassel):
www.uni-kassel.de/uni/fileadmin/datas/uni/presse/anhaenge/2014/01Muda.jpg

Picture of Prof. Dr. Friedrich W. Herberg (Photo: Uni Kassel):
www.uni-kassel.de/uni/fileadmin/datas/uni/presse/anhaenge/2014/02Herberg.jpg

Link to the study: www.pnas.org/content/early/2013/12/17/1312701111.abstract

Contact:

Prof. Dr. Friedrich W. Herberg
University of Kassel
Department of Biochemistry
Tel.: +49 561 804-4511
E-mail: herberg[at]uni-kassel[dot]de

Dipl. Biol. Kathrin Muda
University of Kassel
Department of Biochemistry
Tel.: +49 561 804-4479
E-Mail: kathrinmuda[at]uni-kassel[dot]de