Article (Scientific journals)
Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity.
Stroedicke, Martin; Bounab, Yacine; Strempel, Nadine et al.
2015In Genome Research, 25 (5), p. 701-13
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Keywords :
Algorithms; Amino Acid Sequence; Animals; Brain/metabolism/pathology; Cell Line, Tumor; Drosophila/genetics/metabolism; Huntingtin Protein; Molecular Sequence Data; Nerve Tissue Proteins/chemistry/genetics/metabolism; PC12 Cells; Protein Aggregation, Pathological/metabolism; Protein Binding; Protein Folding; Rats
Abstract :
[en] 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.
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Author, co-author :
Stroedicke, Martin
Bounab, Yacine
Strempel, Nadine
Klockmeier, Konrad
Yigit, Sargon
Friedrich, Ralf P.
Chaurasia, Gautam
Li, Shuang
Hesse, Franziska
Riechers, Sean-Patrick Hermann  ;  Max Delbrueck Center for Molecular Medicine, Neuroproteomics, 13125 Berlin, Germany
Russ, Jenny
Nicoletti, Cecilia
Boeddrich, Annett
Wiglenda, Thomas
Haenig, Christian
Schnoegl, Sigrid
Fournier, David
Graham, Rona K.
Hayden, Michael R.
Sigrist, Stephan
Bates, Gillian P.
Priller, Josef
Andrade-Navarro, Miguel A.
Futschik, Matthias E.
Wanker, Erich E.
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Title :
Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity.
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Journal title :
Genome Research
Publisher :
Cold Spring Harbor Laboratory Press, United States - New York
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Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
© 2015 Stroedicke et al.; Published by Cold Spring Harbor Laboratory Press.
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since 12 September 2023


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