Environment meets genetics: new lessons for Parkinson’s Disease

(cnmpb) Morbus Parkinson, formerly known as agitated paralysis, is a slowly progressing and devastating neurodegenerative disorder. Parkinson’s Disease (PD) has both sporadic (~90%) and familial/genetic (5-10%) origins. Aging still is the major risk factor to develop sporadic forms of the disease. However, some environmental factors, such as exposure to pesticides or metals, are also known to increase the risk to develop of PD. The hereditary form of the disease is based on genetic alterations in the gene encoding for the alpha-synuclein (α-Synuclein) protein.

Scientists of the Göttinger Cluster of Excellence and DFG research center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) at the Universitätsmedizin Göttingen (UMG) now have investigated in trilateral cooperation with the Max Planck Institute for Biophysics, the IIDEFAR Institute in Rosario and the Institute for Neurosciences and Medicine (INM-9) in Jülich the interplay between genetics (mutation of the α-synuclein protein) and the exposure to metals, such as copper or iron.

The authors could show, that that copper significantly alters the aggregation of α-synuclein. Importantly, the study supports the idea that α-synuclein aggregates are not the primary cause of neurotoxicity, opening novel perspectives for therapeutic intervention.

Original publication: Villar-Piqué A, Lopes da Fonseca T, Sant’Anna R, Szegö EM, Fonseca-Ornelas L, Pinho R, Carija A, Gerhardt E, Masaracchia C, Abad Gonzalez E, Rossetti G, Carloni P, Fernández CO, Foguel D, Milosevic I, Zweckstetter M, Ventura S, Outeiro TF (2016) Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity. PNAS, 113(42): E6506-6515.

Synucleinopathies, such as Parkinson’s Disease, comprise a group of progressive disorders characterized by abnormal aggregation and accumulation of the alpha-synuclein protein in the brain. PD is characterized by its typical motor problems (tremor, muscular rigidity, postural instability, and difficulty in initiating movements). In the brain, predominantly dopamine-producing cells are affected, resulting in deficient stimulation of brain regions responsible for motor control.

In the present study the interplay between genetic factors (mutations of α-Synuklein) and the effects of metal exposure has been investigated. The authors found that copper significantly alters the aggregation of alpha-synuclein. Importantly, these finding supports the idea that α-synuclein aggregates are not the primary cause of neurotoxicity, opening novel perspectives for therapeutic intervention.

The laboratory of Prof. Tiago Outeiro (Goettingen) discovered that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q α-synuclein mutation (found in some patients with PD) induces a significant alteration in the propensity of α-synuclein to clump. Copper has formerly described to be associated with neurodegeneration. The H50Q mutation is a disease-inducing mutation, which has been identified in several patients. 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 Profs. Paolo Carloni and Giulia Rossetti in Jülich. “The study demonstrates that interdisciplinary collaboration can indeed bring important insight into disease mechanisms”, says Prof. Outeiro.

The majority of PD cases are sporadic, and environmental factors, such as metal exposure, are thought to play an important role in the disease. Prof. Fernandez explains “Coupling cellular studies with our biophysical approaches confirm the importance of studying the combined effect of multiple factors on protein biology”.

Jr. Prof. Rossetti further explains, “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 α-synuclein. Accessing computational facilities as those we have in Jülich made the difference here: The results obtained by our QM/MM study required almost a dozen million processor hours on the JURECA supercomputers”.

Parkinson’s Disease affects millions of people worldwide. Currently, only symptomatic therapies exist. Thus, there is great need for studies aimed at elucidating the origin of the disease, in order to pioneer the development of novel effective therapeutic strategies.

Prof. Dr. Tiago F. Outeiro is head of the Department of NeuroDegeneration and Restorative Research at the University Medical Center Göttingen. He moreover is a member of the Göttingen Cluster of Excellence and DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB). His research focuses on deciphering the molecular mechanisms that lead to neurodegeneration in devastative diseases such as Parkinson’s, Huntington’s or Alzheimer’s disease.

Prof. Dr. Tiago F. Outeiro
Universitätsmedizin Göttingen, Georg-August-Universität
Department Neurodegeneration and Restorative Research
Phone 0551 / 39-13544, touteir@gwdg.de

CNMPB – Center for Nanoscale Microscopy and Molecular Physiology of the Brain
Cluster of Excellence 171 – DFG Research Center 103
Dr. Heike Conrad
Scientific Program Manager, Press & Public Relations
Humboldtallee 23, 37073 Göttingen

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