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α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies

Abstract

Alterations in α-synuclein dosage lead to familial Parkinson's disease (PD), and its accumulation results in synucleinopathies that include PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Furthermore, α-synuclein contributes to the fibrilization of amyloid-b and tau, two key proteins in Alzheimer's disease, which suggests a central role for α-synuclein toxicity in neurodegeneration. Recent studies of factors contributing to α-synuclein toxicity and its disruption of downstream cellular pathways have expanded our understanding of disease pathogenesis in synucleinopathies. In this Review, we discuss these emerging themes, including the contributions of aging, selective vulnerability and non-cell-autonomous factors such as α-synuclein cell-to-cell propagation and neuroinflammation. Finally, we summarize recent efforts toward the development of targeted therapies for PD and related synucleinopathies.

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Figure 1: Pathways implicated in α-synuclein toxicity.

Kim Caesar/Springer Nature

Figure 2: Therapeutically targeting α-synuclein toxicity.

Kim Caesar/Springer Nature

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Acknowledgements

This work was supported by NIH/NINDS R01 NS076054 (D.K.) and NIH/NINDS 5T32NS041234 (Y.C.W.).

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Y.C.W. and D.K. wrote and reviewed the manuscript.

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Correspondence to Dimitri Krainc.

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Wong, Y., Krainc, D. α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med 23, 1–13 (2017). https://doi.org/10.1038/nm.4269

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