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The concept of alpha-synuclein as a prion-like protein: ten years after

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Abstract

Parkinson’s disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson’s disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson’s disease who had been transplanted over a decade prior to autopsy. We proposed that the Lewy pathology in the grafted neurons was the result of permissive templating or prion-like spread of alpha-synuclein pathology from neurons in the host to those in the grafts. During the following ten years, several studies described the transmission of alpha-synuclein pathology between neurons, both in cell culture and in experimental animals. Recent research has also begun to identify underlying molecular mechanisms. Collectively, these experimental studies tentatively support the idea that the progression from one Braak stage to the next is the consequence of prion-like propagation of Lewy pathology. However, definitive proof that intercellular propagation of alpha-synuclein pathology occurs in Parkinson’s disease cases has proven difficult to secure. In this review, we highlight several open questions that currently prevent us from concluding with certainty that prion-like transfer of alpha-synuclein contributes to the progression of Parkinson’s disease.

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Acknowledgements

We acknowledge the Van Andel Research Institute and the many individuals and corporations that financially support research into neurodegenerative diseases at the Van Andel Research Institute. P.B. is supported by grants from the National Institutes of Health (1R01DC016519-01; 1R21NS105436-01; 5R21NS093993-02) and the Department of Defense (W81XWH-17-1-0535). P.B. also reports additional grants from The Michael J Fox Foundation, National Institutes of Health and Cure Parkinson’s Trust UK.

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  1. Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI, 49503, USA

    Jennifer A. Steiner, Emmanuel Quansah & Patrik Brundin

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  1. Jennifer A. Steiner
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Correspondence to Jennifer A. Steiner.

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P.B. has received commercial support as a consultant from Renovo Neural, Inc., Roche, Cellular Dynamics International Inc., Teva Inc., Lundbeck A/S, AbbVie, ClearView Healthcare, FCB Health, IOS Press Partners and Capital Technologies, Inc. Additionally, he has received commercial support for grants/research from Renovo and Teva/Lundbeck. Furthermore, P.B. has ownership interest in Acousort AB. J.A.S. and E.Q. report no conflicts of interest.

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Steiner, J.A., Quansah, E. & Brundin, P. The concept of alpha-synuclein as a prion-like protein: ten years after. Cell Tissue Res 373, 161–173 (2018). https://doi.org/10.1007/s00441-018-2814-1

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