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| Item Type: | Article |
|---|---|
| Title: | Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity |
| Creators Name: | Stroedicke, M. and Bounab, Y. and Strempel, N. and Klockmeier, K. and Yigit, S. and Friedrich, R.P. and Chaurasia, G. and Li, S. and Hesse, F. and Riechers, S.P. and Russ, J. and Nicoletti, C. and Boeddrich, A. and Wiglenda, T. and Haenig, C. and Schnoegl, S. and Fournier, D. and Graham, R.K. and Hayden, M.R. and Sigrist, S. and Bates, G.P. and Priller, J. and Andrade-Navarro, M.A. and Futschik, M.E. and Wanker, E.E. |
| 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. |
| Keywords: | Algorithms, Amino Acid Sequence, Brain, Molecular Sequence Data, Nerve Tissue Proteins, Pathological Protein Aggregation, PC12 Cells, Protein Binding, Protein Folding, Tumor Cell Line, Animals, Drosophila, Rats |
| Source: | Genome Research |
| ISSN: | 1088-9051 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Volume: | 25 |
| Number: | 5 |
| Page Range: | 701-713 |
| Date: | May 2015 |
| Additional Information: | Copyright © 2015 Stroedicke et al.; Published by Cold Spring Harbor Laboratory Press. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at https://creativecommons.org/licenses/by-nc/4.0/. |
| Official Publication: | https://doi.org/10.1101/gr.182444.114 |
| PubMed: | View item in PubMed |
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