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A 31-residue peptide induces aggregation of tau's microtubule-binding region in cells

Jan Stöhr1,2, Haifan Wu3, Mimi Nick3

  • 1Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94143, USA.

Nature Chemistry
|August 25, 2017
PubMed

Insights

Researchers identified the smallest tau peptide fragment that drives self-propagation in cells, crucial for understanding Alzheimer's disease and developing therapies. This minimal sequence is key to tau aggregation.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Structural Biology

Background:

  • Misfolded tau protein self-propagation drives neurodegenerative diseases like Alzheimer's.
  • The microtubule-binding region (residues 244-372) of tau is implicated in aggregation.
  • Identifying the minimal active nucleus is critical for understanding disease mechanisms.

Purpose of the Study:

  • To determine the minimal sequence and conformational nucleus responsible for tau self-propagation.
  • To investigate how peptide length influences tau aggregation seeding activity.

Main Methods:

  • Peptide synthesis and in vitro fibril formation assays.
  • Cellular assays to assess tau aggregation seeding.
  • X-ray fiber diffraction, hydrogen-deuterium exchange, and solid-state NMR for structural analysis.

Main Results:

  • A hexapeptide from tau's third repeat rapidly formed fibrils but did not seed aggregation in cells.
  • Extending the peptide to 31 residues resulted in slower aggregation but potent seeding activity for tau244-372.
  • Structural studies localized the beta-forming region to a 25-residue sequence.

Conclusions:

  • A small 25-residue peptide contains the nucleus for self-propagating tau aggregation in cells.
  • This minimal sequence is essential for understanding tauopathies and developing targeted interventions.

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