Huntington's disease (HD) is a fatal neurodegenerative disease, for which no cure has yet been found. Although the disease-causing mutation in the huntingtin gene has been identfied for over 20 years, the exact mechanisms that lead to the massive neuronal cell death are still not fully clarified. A variety of processes such as excitotoxicity, protein aggregation and transcriptional dysregulation have been linked to neurodegeneration in HD. More recently, several studies suggested a role of the unfolded protein response (UPR) in neurodegenerative diseases including HD.

The UPR is a complex process that is activated by the accumulation of un- or misfolded proteins in the endoplasmic reticulum (ER). As an adaptive response to counter-balance accumulation of these proteins, the UPR upregulates transcription of chaperones, temporarily attenuates new translation, and activates protein degradation via the proteasome. However, persistent ER stress and an activated UPR can also cause apoptotic cell death. Although different studies have indicated a role for the UPR in HD, the evidence remains inconclusive. Therefore, we carried out extensive bioinformatic analyses that revealed wide-spread UPR activation in different experimental HD models based on publicly available transcriptomic data. The results can be found in Kalathur et al. 2015. Here, we present a companion online tool that enables researchers to search, interactively analyze and visualize the expression patterns of UPR-associated genes across various HD expression data sets.

Analysis & Visualization

HD-related gene expression data were merged for three distinct sets of genes associated with the UPR were defined based on different evidence: (i) UPR-KEGG-GO with 264 genes, (ii) UPR-Interactions with 270 genes, and (iii) UPR-Literature with 1907 genes. Their exact derivation is detailed in the Data & Samples section.

Clicking on one of the button below leads you to the online tool, where the HD expression data of the selected UPR gene set can be queried, visualised and interactively inspected. Another button links to the online for the integrated UPR gene set. An description how to use the online tool for analysis is presented on the Help page.

UPR-KEGG-GO UPR-Interactions UPR-Literature

UPR-Integrated Gene Sets

The visualisation and analysis tool is based on a modified and enhanced version of GeneXplorer application.

Data & Samples

Derivation of gene sets for UPR

Since the UPR is a complex process, it remains difficult to define a unique set of UPR-associated genes. Thus, three alternative sets of genes associated with the UPR were derived based on different evidence:

Details can be found in Table 1 of the publication describing our study of the UPR in HD.

HD gene expression data

HD gene expression data were downloaded from the Gene Expression Ominibus database. These data include gene expression from human brain and blood samples, human iPSCs, mouse, rat and yeast HD models, as well as murine cell lines (see Table below). All expression data sets were pre-processed using RMA (Robust Multi-array Average) implemented in R and analysed using the limma Bioconductor package. Additionally, we included RNA-Seq data measuring the expression in Htt heterozygous mice with different CAG repeat length.

For mapping from different organims to human, the HGNC Comparison of Orthology Predictions (HCOP) search tool was employed. Note, that for the analyses presented in the publication all predicted orthologs were included. For visualization of expression across different organisms by the online tool, however, it is preferrable to reduce the non-unique mappings. Thus, if multiple orthologs were found, we have selected only those with the highest number of supporting prediction algorithms. Furthermore, genes are only visualised if more than 50% of their expression values are present.

GEO ID Comparison Organism Pubmed id
GSE3790 HD caudate nucleus / cerebellum / motor cortex / prefrontal cortex vs control Human 16467349
GSE24250 HD blood vs control Human 21044956
GSE37547 HD iPSC vs corrected iPSC Human 22748967
GSE3583 HdhQ111 striatal cells vs WT Mouse 17708681
GSE3621 R6/1 brain vs WT at 18w, 22w, 27w Mouse 17696994
GSE9760 mESC (CAG150) vs control mESC at 4d, 6d Mouse
GSE9803 R6/2 striatum vs WT at 12w Mouse 17519223
GSE10202 CHL2 striatum vs WT at 22m Mouse 17519223
GSE18551 YAC128 striatum vs WT at 12m, 24m Mouse 20089533
GSE12481 Neuronal culture 82Q vs control Rat 18815258
GSE18644 Htt103Q vs Htt25Q Yeast 21044956


In case that you are using this resource for your research, please quote following reference:

Ravi Kalathur, Joaquin Giner-Lamia, Susana Machado, Tania Barata, Kameshwar Ayasolla and Matthias E. Futschik: The unfolded protein response and its potential role in Huntington's disease elucidated by a systems biology approach. F1000Research 2015, 4:103 ( doi: 10.12688/f1000research.6358.2)