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The Chemistry of Neurodegeneration: Kinetic Data and Their Implications

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Abstract

We collected experimental kinetic rate constants for chemical processes responsible for the development and progress of neurodegeneration, focused on the enzymatic and non-enzymatic degradation of amine neurotransmitters and their reactive and neurotoxic metabolites. A gross scheme of neurodegeneration on the molecular level is based on two pathways. Firstly, reactive species oxidise heavy atom ions, which enhances the interaction with alpha-synuclein, thus promoting its folding to the beta form and giving rise to insoluble amyloid plaques. The latter prevents the function of vesicular transport leading to gradual neuronal death. In the second pathway, radical species, OH· in particular, react with the methylene groups of the apolar part of the lipid bilayer of either the cell or mitochondrial wall, resulting in membrane leakage followed by dyshomeostasis, loss of resting potential and neuron death. Unlike all other central neural system (CNS)-relevant biogenic amines, dopamine and noradrenaline are capable of a non-enzymatic auto-oxidative reaction, which produces hydrogen peroxide. This reaction is not limited to the mitochondrial membrane where scavenging enzymes, such as catalase, are located. On the other hand, dopamine and its metabolites, such as dopamine-o-quinone, dopaminechrome, 5,6-dihydroxyindole and indo-5,6-quinone, also interact directly with alpha-synuclein and reversibly inhibit plaque formation. We consider the role of the heavy metal ions, selected scavengers and scavenging enzymes, and discuss the relevance of certain foods and food supplements, including curcumin, garlic, N-acetyl cysteine, caffeine and red wine, as well as the long-term administration of non-steroid anti-inflammatory drugs and occasional tobacco smoking, that could all act toward preventing neurodegeneration. The current analysis can be employed in developing strategies for the prevention and treatment of neurodegeneration, and, hopefully, aid in the building of an overall kinetic molecular model of neurodegeneration itself.

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Acknowledgements

We would like to thank Prof. Paolo Carloni (German Research School for Simulation Sciences, Jülich, Germany) and Prof. Simon Podnar (Institute for Clinical Neurophysiology, University Medical Centre Ljubljana, Slovenia) for many stimulating discussions. M.R. and J.M. would like to thank the Slovenian Research Agency for the financial support in the framework of the programme group P1–0012 and within the corresponding research project contract No. J1-2014. R.V. gratefully acknowledges the European Commission for an individual FP7 Marie Curie Career Integration Grant (contract number PCIG12-GA-2012-334493). M.P. would like to acknowledge the German Research School for Simulation Sciences (GRS) for the administrative and financial support. M.R. would like to acknowledge Sciex grant 14.141 for financial support. Part of this work was supported by COST Action CM1103. The authors thank Ms. Charlotte Taft for a careful proofreading of the manuscript.

Compliance with Ethical Standards

The authors declare that this entire submission complies with the ethical standards of the journal as there are no conflicts of interest and the research presented here did not involve human participants and/or animals.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Computational Biophysics, German Research School for Simulation Sciences, Joint Venture of RWTH Aachen University and Forschungszentrum Jülich GmbH, 52425, Jülich, Germany

    Matic Pavlin

  2. Computational Biomedicine, Institute for Advanced Simulations (IAS-5/INM-9), 52425, Jülich, Germany

    Matic Pavlin

  3. Laboratory of Computational Chemistry and Biochemistry, Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland

    Matej Repič

  4. Quantum Organic Chemistry Group, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000, Zagreb, Croatia

    Robert Vianello

  5. National Institute of Chemistry, Hajdrihova 19, SI-1000, Ljubljana, Slovenia

    Janez Mavri

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  1. Matic Pavlin
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Pavlin, M., Repič, M., Vianello, R. et al. The Chemistry of Neurodegeneration: Kinetic Data and Their Implications. Mol Neurobiol 53, 3400–3415 (2016). https://doi.org/10.1007/s12035-015-9284-1

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