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

Yuan Yuan Xie, Chen Jie Zhou, Zi Ren Zhou, Jing Hong, Mei Xia Che, Qing Shan Fu, Ai Xin Song, Dong Hai Lin, Hong Yu Hu

Research output: Contribution to journalArticle

33 Scopus citations

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 languageEnglish (US)
Pages (from-to)196-205
Number of pages10
JournalFASEB Journal
Volume24
Issue number1
DOIs
StatePublished - Jan 1 2010

Keywords

  • Coiled coil
  • Dimerization
  • Lewy body
  • N-terminal stretch
  • Parkinson's disease
  • Solution structure

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    Xie, Y. Y., Zhou, C. J., Zhou, Z. R., Hong, J., Che, M. X., Fu, Q. S., Song, A. X., Lin, D. H., & Hu, H. Y. (2010). Interaction with synphilin-1 promotes inclusion formation of α-synuclein: Mechanistic insights and pathological implication. FASEB Journal, 24(1), 196-205. https://doi.org/10.1096/fj.09-133082