Abstract
α-Synuclein (α-Syn) is the major component of Lewy bodies (LBs) deposited in the brains of patients with Parkinson's disease. Synphilin-1 (Sph1) is a novel α-Syn-interacting protein also present in the LBs. However, the roles of α-Syn-Sph1 interaction in LB formation and in the related pathogenesis are still unclear. We have studied the interaction between α-Syn and Sph1 by biochemical and structural approaches and found that the central coiled-coil domain of Sph1 specifically interacts with the N-terminal stretch of α-Syn. When overexpressed in HEK 293T cells, Sph1 forms inclusions together with α-Syn, but the Sph1-positive inclusions cannot recruit the N-terminally truncated α-Syn. The central portion of Sph1 can also recruit α-Syn and induce inclusion formation through its coiled-coil domain. These observations demonstrate that the α-Syn-Sph1 interaction significantly promotes the formation of cytoplasmic α-Syn inclusions, which may have implications for LB formation in neural cells. We have also elucidated solution structure of the coiled-coil domain of Sph1 and its interaction with the N-terminal peptide of α-Syn. The specific interaction between α-Syn and Sph1 provides mechanistic insights into the inclusion-body formation in cells and pathological implication in Parkinson's disease.
Original language | English (US) |
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Pages (from-to) | 196-205 |
Number of pages | 10 |
Journal | FASEB Journal |
Volume | 24 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2010 |
Externally published | Yes |
Keywords
- Coiled coil
- Dimerization
- Lewy body
- N-terminal stretch
- Parkinson's disease
- Solution structure