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Inhibitors of α-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson’s disease and related disorders

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Abstract

An abundance of genetic, histopathological, and biochemical evidence has implicated the neuronal protein, α-synuclein (α-syn) as a key player in the development of several neurodegenerative diseases, the so-called synucleinopathies, of which Parkinson’s disease (PD) is the most prevalent. Development of disease appears to be linked to events that increase the intracellular concentration of α-syn or cause its chemical modification, either of which can accelerate the rate at which it forms aggregates. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or altered forms of α-syn, such as truncations, missense mutations, or chemical modifications by oxidative reactions. Aggregated forms of the protein, especially newly formed soluble aggregates, are toxic to cells, so that one therapeutic strategy would be to reduce the rate at which such oligomerization occurs. We have therefore designed several peptides and also identified small molecules that can inhibit α-syn oligomerization and toxicity in vitro. These compounds could serve as lead compounds for the design of new drugs for the treatment of PD and related disorders in the future.

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Acknowledgments

We thank Michael J. Fox Foundation USA and Research and Development Office, Health and Personal Social Services, Northern Ireland, for their generous financial support.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O.Box: 17666, Al Ain, United Arab Emirates

    Dena A. M. Amer & Omar M. A. El-Agnaf

  2. Division of Psychiatry and Neuroscience, School of Medicine and Dentistry, Queen’s University of Belfast, Whitla Medical Building, Belfast, BT9 7BL, UK

    G. Brent Irvine

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  1. Dena A. M. Amer
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  2. G. Brent Irvine
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  3. Omar M. A. El-Agnaf
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Correspondence to Omar M. A. El-Agnaf.

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Amer, D.A.M., Irvine, G.B. & El-Agnaf, O.M.A. Inhibitors of α-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson’s disease and related disorders. Exp Brain Res 173, 223–233 (2006). https://doi.org/10.1007/s00221-006-0539-y

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