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Citation
Stroedicke, M., Bounab, Y., Strempel, N., Klockmeier, K., Yigit, S., Friedrich, R.P., Chaurasia, G., Li, S., Hesse, F., Riechers, S.P., Russ, J., Nicoletti, C., Boeddrich, A., Wiglenda, T., Haenig, C., Schnoegl, S., Fournier, D., Graham, R.K., Hayden, M.R., Sigrist, S., Bates, G.P., Priller, J., Andrade-Navarro, M.A., Futschik, M.E., Wanker, E.E. (2015). Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity.  Genome Res. 25(5): 701--713.
FlyBase ID
FBrf0230676
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC4417118 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Genome Res.
    Title
    Genome Research
    Publication Year
    1995-
    ISBN/ISSN
    1088-9051
    Data From Reference
    Alleles (6)
    Genes (4)
    Human Disease Models (2)
    Natural transposons (1)
    Insertions (1)
    Experimental Tools (2)
    Transgenic Constructs (5)