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Pathogenic mechanisms
B16 Collapsin response mediator protein 4 downregulates aggregation and toxicity of mutant huntingtin
  1. J Priller1,
  2. C Nicoletti1,
  3. Y Bounab2,
  4. M Grohmann1,
  5. R Foulle2,
  6. J Bieschke2,
  7. C Zabel3,
  8. M Lalowski2,
  9. EE Wanker2
  1. 1Department of Neuropsychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany
  2. 2Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
  3. 3Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany

Abstract

Background Huntington's disease (HD) is an inherited neurodegenerative disorder characterised by the accumulation of N-terminal polyglutamine (polyQ)-containing mutant huntingtin (mHtt) fragments in affected neurons. Several lines of evidence indicate that the process of mHtt misfolding and aggregation is associated with cytotoxicity in HD.

Aims The identification and characterisation of proteins that can modulate this process is critical for understanding HD pathogenesis and the development of novel therapies. The collapsin response mediator protein (CRMP) family mediates many aspects of neuronal development and plasticity by regulating cytoskeleton dynamics. Here, we studied the interaction of CRMP4 with mHtt.

Methods and Results We found that CRMP4 protein levels are strongly reduced in a cell model of HD. By using cell-free and cell-based assays, we demonstrated that CRMP4 reduces polyQ-mediated mHtt aggregation and cytotoxicity. Moreover, we observed that CRMP4 undergoes proteolytic processing by calpain I under toxic mHtt conditions. The truncated CRMP4ΔC499 variant directly interacted with mHtt, and is known to trigger apoptosis.

Conclusion Our results suggest a novel role for CRMP4 in HD pathogenesis.

Funding Funded by NGFN Plus (BMBF).

  • Polyglutamine
  • PC12 cells
  • R6/2 transgenic mice
  • calpain
  • apoptosis

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