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Synphilin-1 associates with α-synuclein and promotes the formation of cytosolic inclusions

Abstract

Parkinson disease (PD) is a neurodegenerative disease characterized by tremor, bradykinesia, rigidity and postural instability. Post-mortem examination shows loss of neurons and Lewy bodies, which are cytoplasmic eosinophilic inclusions, in the substantia nigra and other brain regions1,2. A few families have PD caused by mutations (A53T or A30P) in the gene SNCA (encoding α-synuclein; refs 3, 4, 5). α-synuclein is present in Lewy bodies of patients with sporadic PD (Refs 6,7), suggesting that α-synuclein may be involved in the pathogenesis of PD. It is unknown how α-synuclein contributes to the cellular and biochemical mechanisms of PD, and its normal functions and biochemical properties are poorly understood8,9,10. To determine the protein-interaction partners of α-synuclein, we performed a yeast two-hybrid screen. We identified a novel interacting protein, which we term synphilin-1 (encoded by the gene SNCAIP). We found that α-synuclein interacts in vivo with synphilin-1 in neurons. Co-transfection of both proteins (but not control proteins) in HEK 293 cells yields cytoplasmic eosinophilic inclusions.

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Figure 1: Association of α-synuclein with synphilin-1 in yeast.
Figure 2: Synphilin-1 ORF.
Figure 3: Interaction of α-synuclein and synphilin-1.
Figure 4: Expression pattern of synphilin-1 and co-localization with α-synuclein.
Figure 5: Formation of cytoplasmic inclusions by co-transfection of constructs encoding NAC and synphilin-1.

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Acknowledgements

We thank G.L. Rudow and C. Zhang for technical support, B.E. Hoffman for providing the primary cultures and M. Delanoy for the assistance with confocal microscopy. This work was supported by a grant from the Parkinson's Disease Foundation, a Pew Fellows Award to S.E., NINDS NS38377 and NS16375, the DeVelbiss fund and a bequest from Sar and Brita Levitan. X.G. is supported by the Herbert Friedburg Fellowship and T.M.D. and V.L.D. are supported by the Edward D. and Anna Mitchell Family Foundation.

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Correspondence to Christopher A. Ross.

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Engelender, S., Kaminsky, Z., Guo, X. et al. Synphilin-1 associates with α-synuclein and promotes the formation of cytosolic inclusions. Nat Genet 22, 110–114 (1999). https://doi.org/10.1038/8820

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