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Monoclonal antibodies recognize distinct conformational epitopes formed by polyglutamine in a mutant huntingtin

Justin Legleiter1, Gregor P Lotz, Jason Miller

  • 1Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.

The Journal of Biological Chemistry
|June 4, 2009
PubMed

Insights

Huntington disease (HD) therapies may target toxic huntingtin (htt) protein conformations. Specific antibodies targeting polyglutamine (polyQ) domains inhibited htt aggregation and disaggregated existing fibrils, offering new therapeutic strategies.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Huntington disease (HD) is a neurodegenerative disorder.
  • It is caused by expanded polyglutamine (polyQ) domains in the huntingtin (htt) protein.
  • Expanded polyQ htt aggregates into toxic inclusion bodies.

Purpose of the Study:

  • To investigate the effect of anti-htt antibodies on mutant htt aggregate formation and stability.
  • To analyze the different conformations of expanded polyQ domains in solution.

Main Methods:

  • Atomic force microscopy was used to analyze the effect of anti-htt antibodies.
  • A panel of anti-htt antibodies (MW1-MW5, MW7, MW8, and 3B5H10) were tested.
  • The stability of a mutant htt-exon1 fragment was assessed.

Main Results:

  • Two antibodies, MW7 (polyproline-specific) and 3B5H10 (polyQ-specific), completely inhibited fibril formation.
  • These antibodies also disaggregated preformed htt fibrils.
  • Other polyQ-specific antibodies showed varied effects on aggregation.

Conclusions:

  • Expanded polyQ domains adopt multiple conformations in solution.
  • These conformations can be distinguished by specific monoclonal antibodies.
  • Findings have implications for understanding polyQ toxicity and developing antibody-based HD therapeutics.

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