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On the key role played by altered protein conformation in Parkinson’s disease

  • Parkinson's Disease and Allied Conditions - Review Article
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Abstract

On the basis of the previously proposed hierarchic organisation of the central nervous system (CNS) and of its syntropic behaviour, a view of neurodegenerative diseases focusing on the assemblage of abnormal multimeric proteins (pathologic protein mosaics (PMs)) is proposed. Thus, the main focus of the present paper is on Parkinson’s disease (PD) as a neurodegenerative disease, which has as crucial feature protein conformational alterations and formation of pathological PMs. Two interconnected cellular dysfunctions are discussed as main pathogenic factors of PD syndromes, namely mitochondrial deficits (i.e. energy failure, especially critical for Substantia Nigra DA neurons) and conformational protein alterations (due to genetic or environmental causes). Conformational protein alterations can trigger pathological phenomena via the loss and/or the gain of new functions. In particular, altered proteins can lead to the formation of abnormal PMs, which can, inter alia, cause distortion of cellular structures, toxic functions and/or formation of improper membrane ion channels. In view of the fact that disordered proteins can easily acquire unwanted conformation, the “disorder index” (DI) for proteins involved in PD has been evaluated. It has been found that both α-synuclein and tau-protein have high DI. This datum is in agreement with the observation that these two proteins synergistically promote polymerisation of each other into amyloid fibrils, favouring the formation of Lewy bodies.

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Acknowledgments

The work has been supported by an IRCCS and a PRIN grant. Thanks to Dott. A. Percesepe (Dep. of Medical Genetic) for suggestions on the Table.

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Authors and Affiliations

  1. Section of Physiology, Department of Biomedical Sciences, University of Modena, 41100, Modena, Italy

    L. F. Agnati, E. Baldelli, N. Andreoli & V. Vellani

  2. Behavioural Neuroscience Branch, National Institute on Drug Abuse, NIH, DHHS, Baltimore, MD, 20817, USA

    A. S. Woods

  3. Department of Neuroscience, Division of Cellular and Molecular Neurochemistry, Karolinska Institute, 171 77, Stockholm, Sweden

    D. Marcellino & K. Fuxe

  4. Department of Anatomy and Physiology, University of Padua, 35121, Padua, Italy

    D. Guidolin

  5. IRCCS, San Camillo, 30126, Venice, Italy

    L. F. Agnati

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  1. L. F. Agnati
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Agnati, L.F., Baldelli, E., Andreoli, N. et al. On the key role played by altered protein conformation in Parkinson’s disease. J Neural Transm 115, 1285–1299 (2008). https://doi.org/10.1007/s00702-008-0072-1

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