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

FASEB J. 2010 Jan;24(1):196-205. doi: 10.1096/fj.09-133082. Epub 2009 Sep 17.


alpha-Synuclein (alpha-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 alpha-Syn-interacting protein also present in the LBs. However, the roles of alpha-Syn-Sph1 interaction in LB formation and in the related pathogenesis are still unclear. We have studied the interaction between alpha-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 alpha-Syn. When overexpressed in HEK 293T cells, Sph1 forms inclusions together with alpha-Syn, but the Sph1-positive inclusions cannot recruit the N-terminally truncated alpha-Syn. The central portion of Sph1 can also recruit alpha-Syn and induce inclusion formation through its coiled-coil domain. These observations demonstrate that the alpha-Syn-Sph1 interaction significantly promotes the formation of cytoplasmic alpha-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 alpha-Syn. The specific interaction between alpha-Syn and Sph1 provides mechanistic insights into the inclusion-body formation in cells and pathological implication in Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Dimerization
  • Humans
  • Inclusion Bodies / metabolism*
  • Inclusion Bodies / pathology
  • Lewy Bodies / metabolism
  • Lewy Bodies / pathology
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Magnetic Resonance, Biomolecular
  • Parkinson Disease / etiology
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Protein Interaction Domains and Motifs
  • Protein Structure, Quaternary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Static Electricity
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • Carrier Proteins
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • Recombinant Proteins
  • SNCAIP protein, human
  • alpha-Synuclein

Associated data

  • PDB/2JN5
  • PDB/2KES