Tau Interacts with the C-Terminal Region of α-Synuclein, Promoting Formation of Toxic Aggregates with Distinct Molecular Conformations

Biochemistry. 2019 Jun 25;58(25):2814-2821. doi: 10.1021/acs.biochem.9b00215. Epub 2019 Jun 7.

Abstract

An increasing body of evidence suggests that aggregation-prone proteins associated with various neurodegenerative diseases synergistically promote their mutual aggregation, leading to the co-occurrence of multiple neurodegenerative diseases in the same patient. Here we investigated teh molecular basis of synergistic interactions between the two pathological proteins, tau and α-synuclein, using various biophysical techniques including transmission electron microscopy (TEM), circular dichroism (CD), and solution and solid-state NMR. Our biophysical analyses of α-synuclein aggregation in the absence and presence of tau reveal that tau monomers promote the formation of α-synuclein oligomers and subsequently fibril formation. Solution NMR results also indicate that monomeric forms of tau selectively interact with the C-terminal region of the α-synuclein monomer, accelerating α-synuclein aggregation. In addition, a combined use of TEM and solid-state NMR spectroscopy reveals that the synergistic interactions lead to the formation of toxic α-synuclein aggregates with a distinct morphology and molecular conformation. The filamentous α-synuclein aggregates as well as α-synuclein monomers were also able to induce tau aggregation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Circular Dichroism
  • Humans
  • Microscopy, Electron, Transmission
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Aggregates*
  • Protein Conformation
  • Protein Multimerization
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / metabolism*
  • tau Proteins / chemistry
  • tau Proteins / metabolism*

Substances

  • MAPT protein, human
  • Protein Aggregates
  • SNCA protein, human
  • alpha-Synuclein
  • tau Proteins