Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity

Martin Stroedicke, Yacine Bounab, Nadine Strempel, Konrad Klockmeier, Sargon Yigit, Ralf P Friedrich, Gautam Chaurasia, Shuang Li, Franziska Hesse, Sean-Patrick Riechers, Jenny Russ, Cecilia Nicoletti, Annett Boeddrich, Thomas Wiglenda, Christian Haenig, Sigrid Schnoegl, David Fournier, Rona K Graham, Michael R Hayden, Stephan SigristGillian P Bates, Josef Priller, Miguel A Andrade-Navarro, Matthias E Futschik, Erich E Wanker

Research output: Contribution to journalArticlepeer-review

Abstract

Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region-specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins.

Original languageEnglish
Pages (from-to)701-13
Number of pages13
JournalGenome Research
Volume25
Issue number5
DOIs
Publication statusE-pub ahead of print - 23 Apr 2015

Keywords

  • Algorithms
  • Amino Acid Sequence
  • Animals
  • Brain
  • Cell Line, Tumor
  • Drosophila
  • Huntingtin Protein
  • Molecular Sequence Data
  • Nerve Tissue Proteins
  • PC12 Cells
  • Protein Aggregation, Pathological
  • Protein Binding
  • Protein Folding
  • Rats
  • Journal Article
  • Research Support, Non-U.S. Gov't

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