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Parkin ubiquitinates the α-synuclein–interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease

Abstract

Parkinson disease is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic-ubiquitinated inclusions (Lewy bodies). Mutations in α-synuclein (A53T, A30P) and parkin cause familial Parkinson disease. Both these proteins are found in Lewy bodies. The absence of Lewy bodies in patients with parkin mutations suggests that parkin might be required for the formation of Lewy bodies. Here we show that parkin interacts with and ubiquitinates the α-synuclein–interacting protein, synphilin-1. Co-expression of α-synuclein, synphilin-1 and parkin result in the formation of Lewy-body–like ubiquitin-positive cytosolic inclusions. We further show that familial-linked mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions. These results provide a molecular basis for the ubiquitination of Lewy-body–associated proteins and link parkin and α-synuclein in a common pathogenic mechanism through their interaction with synphilin-1.

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Figure 1: Parkin fails to interact with and ubiquitinate non-glycosylated α-synuclein.
Figure 2: Parkin interacts with the α-synuclein–interacting protein, synphilin-1.
Figure 3: Co-immunoprecipitation of synphilin-1 and parkin in rat brain extract.
Figure 4: Synphilin-1 interacts preferentially with the C-terminal R2 ring-finger domain of parkin and parkin interacts with the ankyrin domain of synphilin-1.
Figure 5: Familial-associated mutations in parkin alter the interaction and ubiquitination of synphilin-1.
Figure 6: Parkin ubiquitinates Lewy-body–like inclusions that are formed when synphilin-1 and α-synuclein are co-expressed.

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Acknowledgements

This work was supported by USPHS grant NS38377 and the Edward D. and Anna Mitchell Family Foundation.

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Correspondence to Ted M. Dawson.

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Chung, K., Zhang, Y., Lim, K. et al. Parkin ubiquitinates the α-synuclein–interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 7, 1144–1150 (2001). https://doi.org/10.1038/nm1001-1144

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