Research into the molecular causes of Huntington's Disease (HD) has delivered a wealth of data. Although these data have the potential to give us many new insights into disease-relevant mechanisms, their immediate interpretation remains challenging. This is especially the case for data generated by high-throughput technologies that can monitor the abundance of thousands of genes or proteins simultaneously. In contrast, the relations between these genes or proteins are generally not at all or only poorly known. As many phenotypic changes are, however, not simply due to the change of activity of individual genes, but are caused by cohesive alterations in complex molecular networks, the lack of knowledge of the underlying network has severely restricted the ability of researchers to fully utilize the generated data.
Thus, to facilitate researchers' interpretation and utilization of biological data, we have developed a web-server for the query and visualization of HD-related molecular networks. The software (HDNetDB) provides HD researchers an easy but powerful tool for visualisation of molecular networks and identification of potential targets for therapeutic intervention. The advantages for researchers are that i) complex network information is more readily accessible, ii) HD-related molecular processes can be presented in a more comprehensive manner, iii) additional data e.g. from drug screens can immediately placed in the molecular context, and iv) potential causes and effects can more easily distinguished. Notably, we have customized this interface to needs of HD researchers, especially with respect to identification of disease processes and new drug targets.
Additionally, we have carried out computational analyses of HD-related molecular mechanisms. Although HD is a classical Mendelian disorder i.e. it is caused by the mutation in a single gene, our analyses showed that numerous processes are involved on the molecular level (BMC Neurology, 2012). The large variability in the pathogenesis of HD strongly indicates that apart from the disease-causing poly-Q expansion - other modifying factors exist. Using an integrative approach, we could identify several promising candidates for disease modifiers, which might open new avenues for therapies (BMC Neurology, 2012). A special focus in the project was set on the Unfolded Protein Response (UPR) and its potential implication in HD. Here, our investigations strongly indicate the conserved activation of the UPR in various HD models. More importantly, we could identify key genes that provide a potential link between UPR and HD as well as a connection to programmed cell death. These genes could serve as valuable therapeutic targets for future investigations (F1000Research). A recently developed web-tool termed (UPR-HD) provides researchers direct access to the integrated expression data for UPR-related genes across different HD models and in HD patients.
Ravi Kiran Reddy Kalathur, José Pedro Pinto, Biswanath Sahoo, Gautam Chaurasia and Matthias E. Futschik, HDNetDB: A Molecular Interaction Database for network-oriented investigations into Huntington's Disease, in revision
Ravi KR Kalathur, Joaquin Giner-Lamia, Susana Machado, Kameshwar RS Ayasolla, Matthias E. Futschik , The unfolded protein response and its potential role in Huntington ´s disease elucidated by a systems biology approach, F1000Research 4:103(html+pdf)
Ravi Kalathur, Miguel Hernandez-Prieto and Matthias E. Futschik (2012) Huntington´s Disease and its target genes: A global functional profile based on the HD Research Crossroads database, BMC Neurology 12:47 (html+pdf, Supplementary Material))
Ravi Kalathur, Kameshwar Ayasolla and Matthias Futschik (2012) The Unfolded Protein Response and its potential role in Huntington's disease; Nature Precedings; dx.doi.org/10.1038/npre.2012.7145.1 (html)Matthias Futschik (2010) Chorea Huntington: A thousand changes due to a single mutation, Contributed Talk, 2nd Meeting of the Institute for Biotechnology and Bioengineering, Universidade do Minho, Braga, Portugal (pdf) Ravi K Kalathur and Matthias.E. Futschik (2010) Network-based analyses of Huntington's disease; Nature Precedings; dx.doi.org/10.1038/npre.2012.7078.1 (html)
Kameshwar Ayasolla, Ravi Kalathur and Matthias Futschik (2010) A systems biology approach towards deciphering the unfolded protein response in Huntington's disease; Nature Precedings; dx.doi.org/10.1038/npre.2012.7078.1 (html)
Kameshwar Ayasolla, Ravi Kalathurand Matthias Futschik (2010) ER stress: an initiator of neuroinflammation in Huntington's disease? J Neurol Neurosurg Psychiatry 81:A5 doi:10.1136/jnnp.2010.222570.16 (abstract)Ravi K Kalathur,Gautam Chaurasia, Erich Wanker and Matthias.E. Futschik (2010) Molecular interaction networks in Huntington´s Disease, SINAL 2010, Faro, Portugal