title: Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity.
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.
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Stroedicke
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Yacine
authors.initials: Y
authors.lastname: Bounab
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Nadine
authors.initials: N
authors.lastname: Strempel
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Konrad
authors.initials: K
authors.lastname: Klockmeier
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Sargon
authors.initials: S
authors.lastname: Yigit
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Friedrich
authors.affiliation: Institute of Theoretical Biology, Humboldt University of Berlin, 10115 Berlin, Germany;
authors.forename: Gautam
authors.initials: G
authors.lastname: Chaurasia
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Franziska
authors.initials: F
authors.lastname: Hesse
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Sean-Patrick
authors.initials: SP
authors.lastname: Riechers
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Jenny
authors.initials: J
authors.lastname: Russ
authors.affiliation: Department of Neuropsychiatry, Charité-Universitaetsmedizin Berlin, 10117 Berlin, Germany;
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nicoletti
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Annett
authors.initials: A
authors.lastname: Boeddrich
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiglenda
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Christian
authors.initials: C
authors.lastname: Haenig
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Sigrid
authors.initials: S
authors.lastname: Schnoegl
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: David
authors.initials: D
authors.lastname: Fournier
authors.affiliation: Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada;
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.affiliation: Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada;
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Institute of Biology/Genetics, Free University Berlin, 14195 Berlin, Germany;
authors.forename: Stephan
authors.initials: S
authors.lastname: Sigrist
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, United Kingdom;
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.affiliation: Department of Neuropsychiatry, Charité-Universitaetsmedizin Berlin, 10117 Berlin, Germany;
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Andrade-Navarro
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany; Centre for Molecular and Structural Biomedicine, Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal.
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Futschik
authors.affiliation: Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany;
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D000071058:Huntingtin Protein; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D051381:Rats; D000098855:Collapsin Response Mediator Protein 1
chemical_list: D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; C102924:CRMP1 protein, human; D000098855:Collapsin Response Mediator Protein 1; C086055:HTT protein, human