Environment meets genetics: New lessons for Parkinson’s disease


FZ Jülich, a BioExcel partner, is using CPMD, a leading QM/MM software package, to understand more about how Parkinson’s disease develops.

Parkinson’s disease (PD) is a devastating disorder, affecting a growing number of people worldwide, due to the overall aging of the human population. The disease is known for its typical motor problems (tremor, muscular rigidity, postural instability, and difficulty in initiating movements), although it is also characterized by several other non-motor symptoms that can be highly debilitating. In the brain, the cells that produce dopamine are mostly affected, resulting in deficient stimulation of brain regions responsible for motor control.

 

Can a single protein shed light into Parkinson’s disease?

When researchers study the brains of individuals who had PD, they find the accumulation of protein clumps made of a protein known as alpha-synuclein. This happens for reasons we do not fully understand, although in a small percentage of Parkinson’s cases, genetic alterations can be found in the gene.

Alpha-synuclein was first associated with PD almost 20 years ago, but we are still in the early days of understanding the mechanisms by which the protein causes disease.

The Institute of Computational Biomedicine IAS-5/INM-9 in Forschungszentrum Jülich, one of the main BioExcel partners, in a trilateral collaboration between the University Medical Center of Goettingen, the Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics and the IIDEFAR Institute in Rosario, cast new light on how the protein works and on the interplay between environmental and intrinsic factors contributing to AS aggregation.

The laboratory of Prof. Tiago Outeiro (Goettingen) discovered that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q alpha-synuclein mutation (found in some patients with PD) induces a significant alteration in the propensity of alpha-synuclein to clump. Then, the molecular rationale of the interaction between H50 and copper atoms was provided by the integration of structural data obtained in the laboratory of Prof. Claudio Fernandez in Rosario, with simulations from Prof. Paolo Carloni’s team in Jülich.

The study demonstrates that interdisciplinary collaboration can indeed bring important insight into disease mechanisms.

The majority of PD cases are sporadic, and environmental factors, such as metal exposure, are thought to play an important role in the disease.

Coupling cellular studies with our biophysical approaches confirm the importance of studying the combined effect of multiple factors on protein biology.

In particular, the so-called hybrid quantum mechanical/molecular mechanics (QM/MM) simulation, whose relevance for molecular modeling has been recognized by a recent Nobel Prize in Chemistry, is arguably the method of choice to predict the complex interactions and spectroscopic properties of complex transition metal ions-based proteins such as copper(II) ions bound to alpha-synuclein. Accessing computational facilities as those we have in Juelich made the difference here: The results obtained by our QM/MM study required almost a dozen million processor hours on the JURECA supercomputers (http://www.fz-juelich.de/ias/jsc/EN/Expertise/Supercomputers/JURECA/JURECA_node.html).

PD affects millions of people worldwide and has only symptomatic therapies at the moment. Thus, there is great need for studies aimed at elucidating the origin of the disease, such as the one now published by the German-Argentinian researchers, in order to bring us closer to the development of novel effective therapeutic strategies.

REFERENCE

Villar-Piqué A., et al., Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity. Proceedings of the National Academy of Sciences (PNAS) USA 2016. 113(42): E6506-E6515.
Epub 2016 Oct 5

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