Interaction with synphilin-1 promotes inclusion formation of α-synuclein: mechanistic insights and pathological implication.

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 Sphl 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 Sphl and its interaction with the N-terminal peptide of α-Syn. The specific interaction between α-Syn and Sphl provides mechanistic insights into the inclusion-body formation in cells and pathological implication in Parkinson's disease. [ABSTRACT FROM AUTHOR]