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α-Synuclein Elevation in Human Neurodegenerative Diseases: Experimental, Pathogenetic, and Therapeutic Implications

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Abstract

The discovery of α-synuclein has had profound implications concerning our understanding of Parkinson’s disease (PD) and other neurodegenerative disorders characterized by α-synuclein accumulation. In fact, as compared with pre-α-synuclein times, a “new” PD can now be described as a whole-body disease in which a progressive spreading of α-synuclein pathology underlies a wide spectrum of motor as well as nonmotor clinical manifestations. Not only is α-synuclein accumulation a pathological hallmark of human α-synucleinopathies but increased protein levels are sufficient to trigger neurodegenerative processes. α-Synuclein elevations could also be a mechanism by which disease risk factors (e.g., aging) increase neuronal vulnerability to degeneration. An important corollary to the role of enhanced α-synuclein in PD pathogenesis is the possibility of developing α-synuclein-based biomarkers and new therapeutics aimed at suppressing α-synuclein expression. The use of in vitro and in vivo experimental models, including transgenic mice overexpressing α-synuclein and animals with viral vector-mediated α-synuclein transduction, has helped clarify pathogenetic mechanisms and therapeutic strategies involving α-synuclein. These models are not devoid of significant limitations, however. Therefore, further pursuit of new clues on the cause and treatment of PD in this post-α-synuclein era would benefit substantially from the development of improved research paradigms of α-synuclein elevation.

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Acknowledgments

The authors thank Dr. Sarah Jewell for her comments on the manuscript. This work was supported by the Centres of Excellence in Neurodegeneration Research (CoEN) and the Blanche A. Paul Foundation.

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The authors declare that they have no conflict of interest.

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  1. German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany

    Ayse Ulusoy & Donato A. Di Monte

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Correspondence to Donato A. Di Monte.

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Ulusoy, A., Di Monte, D.A. α-Synuclein Elevation in Human Neurodegenerative Diseases: Experimental, Pathogenetic, and Therapeutic Implications. Mol Neurobiol 47, 484–494 (2013). https://doi.org/10.1007/s12035-012-8329-y

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  • DOI: https://doi.org/10.1007/s12035-012-8329-y

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