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Interaction with synphilin‐1 promotes inclusion formation of α‐synuclein: mechanistic insights and pathological implication
Author(s) -
Xie Yuan-Yuan,
Zhou Chen-Jie,
Zhou Zi-Ren,
Hong Jing,
Che Mei-Xia,
Fu Qing-Shan,
Song Ai-Xin,
Lin Dong-Hai,
Hu Hong-Yu
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-133082
Subject(s) - inclusion bodies , hek 293 cells , chemistry , pathogenesis , coiled coil , microbiology and biotechnology , cytoplasm , biology , biochemistry , receptor , gene , immunology , escherichia coli
α‐Synuclein (α‐Syn) is the major component of Lewy bodies (LBs) deposited in the brains of patients with Parkinson's disease. Synphilin‐1 (Sphl) is a novel α‐Syn‐interacting protein also present in the LBs. However, the roles of α‐Syn‐Sphl 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, Sphl forms inclusions together with α‐Syn, but the Sphl‐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‐Sphl 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.—Xie, Y.‐Y., Zhou, C.‐J., Zhou, Z.‐R., Hong, J., Che, M.‐X., Fu, Q.‐S., Song, A.‐X., Lin, D.‐H., and Hu, H.‐Y. Interaction with synphi‐lin‐l promotes inclusion formation of α‐synuclein: mechanistic insights and pathological implication. FASEB J . 24, 196–205 (2010). www.fasebj.org