Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity
Year: 2015
Type: preprint
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.
Source: Genome Research
Authors: 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 Sigrist, Gillian P. Bates, Josef Priller, Miguel A. Andrade-Navarro, Matthias E. Futschik, Erich E. Wanker
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
Awards: G1351906726, G145143448, G1657632943, G253050166, Verbundprojekt Neurodegeneration: Bioinformatik-gestützte Analyse und Interpretation von Phänotyp/Genotyp-Relationen bei neurodegenerativen Erkrankungen., European Consortium on Synaptic Protein Networks in Neurological and Psychiatric Diseases, G4662980202, G6174327408, Synaptic Systems: dissecting brain function in health and disease, G6742686329, Verbundprojekt: Systembiologie genetisch bedingter Erkrankungen - Mutanom: Anteil MDC Berlin-Buch (Teilprojekt 6), G822600927, G8658714124, G884619906, Verbundprojekt: Molekulare Ursachen von Affektiven Störungen und Schizophrenie 'MooDS' - Teilprojekt 11: Erstellung von Protein-Protein Interaktionsnetzwerken für psychiatrische Erkrankungen
OpenAlex ID: W2108504121