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On the trail of Parkinson's disease

Chemists from Konstanz prove what happens when selective mutations occur to alpha-synuclein protein

Date:
March 24, 2017
Source:
University of Konstanz
Summary:
The molecular causes of diseases such as Parkinson's need to be understood as a first step towards combating them. Chemists recently succeeded in analyzing what happens when selective mutations of the alpha-synuclein protein occur -- a protein that is closely linked to Parkinson's disease.
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In a complex series of experiments they examined what the effects were of changing a single amino acid in the protein. The physicochemists were able to prove how this tiny change disturbs the binding of alpha-synuclein to membranes. "We hope that the finding of this selectively defective membrane binding will help us to understand how Parkinson's develops on a molecular level. Ultimately, this will facilitate the devising of therapeutic strategies," outlines Julia Cattani, a doctoral student, who played a major role in the success of the research. The research results were revealed in the Journal of the American Chemical Society publication in its 16 March 2017 online edition; a print version is to follow.

The human brain contains large quantities of the small alpha-synuclein protein. Its exact biological function is still unknown, yet it is closely linked to Parkinson's disease; the protein "clumps together" in the nerve cells of Parkinson patients. Alpha-synuclein consists of a chain of 140 amino acids. In rare cases Parkinson's disease is hereditary; where this occurs one of these 140 components has been replaced. Malte Drescher and his working group in the Department of Chemistry at the University of Konstanz have now found out the influence these selective changes in the protein sequence can have on the behaviour of alpha-synuclein. "We can show that the selective mutations disturb the membrane binding of alpha-synuclein on a local level," explains Malte Drescher.

To find out more about the influence of selective mutations, the Konstanz-based chemists Dr Marta Robotta and Julia Cattani applied tiny magnetic probe molecules to various places on the alpha-synuclein protein. With the help of electron paramagnetic resonance spectroscopy -- a procedure similar in method to magnetic resonance imaging (MRI) used in the medical field -- the researchers were able to measure the rotation of these nanomagnets. At every residue at which alpha-synuclein binds to a membrane, the rotation slows down. In this way they were able to find out precisely when and where a binding to the membranes takes place -- and when it does not. In the case of the exchanged amino acids the physicochemists from Konstanz discovered a disturbance of the membrane binding of alpha-synuclein -- an important clue for the molecular context of Parkinson's disease.

"We went to great lengths, performing over 200 spectroscopic experiments, the results of which we compared with our models by means of a specially developed simulation algorithm. The outcome certainly compensated our efforts," says Julia Cattani. Project leader Malte Drescher believes that alongside the huge commitment of his staff, an important prerequisite for the success of the research was, above all, the environment of the Collaborative Research Centre (SFB) 969, "Chemical and biological principles of cellular proteostasis" which formed the basis for sponsoring the project: "By networking on an interdisciplinary level and discussing with colleagues we managed to solve the many problems we faced," emphasises Malte Drescher.


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Materials provided by University of Konstanz. Note: Content may be edited for style and length.


Journal Reference:

  1. Marta Robotta, Julia Cattani, Juliana Cristina Martins, Vinod Subramaniam, Malte Drescher. Alpha-Synuclein Disease Mutations Are Structurally Defective and Locally Affect Membrane Binding. Journal of the American Chemical Society, 2017; DOI: 10.1021/jacs.6b05335

Cite This Page:

University of Konstanz. "On the trail of Parkinson's disease." ScienceDaily. ScienceDaily, 24 March 2017. <www.sciencedaily.com/releases/2017/03/170324104833.htm>.
University of Konstanz. (2017, March 24). On the trail of Parkinson's disease. ScienceDaily. Retrieved March 28, 2024 from www.sciencedaily.com/releases/2017/03/170324104833.htm
University of Konstanz. "On the trail of Parkinson's disease." ScienceDaily. www.sciencedaily.com/releases/2017/03/170324104833.htm (accessed March 28, 2024).

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