Huntington’s disease is a neurodegenerative disorder characterized by huntingtin protein aggregates in a patient’s brain, but how these aggregates form is not well understood. In a study published online today in Genome Research, researchers developed a novel computational strategy to identify interaction partners of the huntingtin protein and discovered a novel factor that suppresses misfolding and aggregation.
Huntington’s disease is caused by an expansion of glutamine residues in the huntingtin protein, altering its function and ultimately resulting in toxic aggregation of huntingtin fragments in neurons. Proteins that interact with the glutamine-expanded huntingtin protein are thought to strongly influence the formation of the aggregates.
“The challenge that remains is if there are many proteins interacting with the huntingtin protein, we cannot easily determine which are relevant for disease and which are not,” said Erich Wanker from Max Delbrück Center for Molecular Medicine and corresponding author of the study.
By combining large datasets of protein-protein interactions and filtering by brain-specific gene expression in patients with and without Huntington’s disease, the scientists narrowed potential interactors to 13 candidates, including 7 that are known targets in Huntington’s disease.
The researchers followed up on one candidate, CRMP1, because of its expression in brain and not elsewhere in the body. Using cell-based model systems and Drosophila, they found CRMP1 overexpression reduces hungtingtin aggregation and cellular toxicity, while reduced CRMP1 results in increased aggregation and toxicity. In cell-free assays, CRMP1 slows the spontaneous self-assembly of huntingtin fragments with glutamine expansions.
“CRMP1 was not regarded as a therapeutic target so far, now it is worth exploring as a potential target,” said Wanker.
Scientists from Max Delbrück Center for Molecular Medicine, Humbold University of Berline, Charté-Universitaetsmedizin Berlin, University of British Columbia, Free University of Berlin, King’s College London, and University of Algarve contributed to this study.
Funding: This research was funded by the Deutsche Forschungsgemeinschaft (DFG), the Federal Ministry of Education and Research (BMBF), HDSA Coalition for the Cure, the European Union, and the Helmholtz Association.
Source: Peggy Calicchia – Cold Spring Harbor Laboratory
Image Source: Image courtesy of Nadine Strempel and Erich Wanker, Max Delbrück Center for Molecular Medicine.
Original Research: Abstract for “Systematic interaction network filtering identifies CRMP1 as a novel suppressor of Huntingtin misfolding and neurotoxicity” by 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, and Erich E. Wanker in Genome Research. Published online April 23 2015 doi:10.1101/gr.182444.114
Abstract
Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity
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.
“Systematic interaction network filtering identifies CRMP1 as a novel suppressor of Huntingtin misfolding and neurotoxicity” by 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, and Erich E. Wanker in Genome Research. Published online April 23 2015 doi:10.1101/gr.182444.114
