Abstract
Huntington ´s disease (HD) is a progressive, neurodegenerative disease with a fatal outcome. Although the disease-causing gene (huntingtin) has been known for over 20 years, the exact mechanisms leading to neuronal cell death are still controversial. One potential mechanism contributing to the massive loss of neurons observed in the brain of HD patients could be the unfolded protein response (UPR) activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). As an adaptive response to counter-balance accumulation of un- or misfolded 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. Here, we present extensive bioinformatic analyses that revealed UPR activation in different experimental HD models based on transcriptomic data. Accordingly, we have identified 58 genes, including RAB5A, HMGB1, CTNNB1, DNM1, TUBB, TSG101, EEF2, DYNC1H1 and SLC12A5 that provide a potential link between UPR and HD. To further elucidate the potential role of UPR as a disease-relevant process, we examined its connection to apoptosis based on molecular interaction data, and identified a set of 40 genes including ADD1, HSP90B1, IKBKB, IKBKG, RPS3A and LMNB1, which seem to be at the crossroads between these two important cellular processes.
Highlights
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder
Since changes in gene transcription are main effects of unfolded protein response (UPR) activation and published microarray data are available for HD in humans as well as for HD models, we collected 12 different gene expression datasets generated for the study of HD: three datasets included expression from human blood and brain samples as well as human induced pluripotent stem cells; seven datasets were derived from HD mouse models and cell cultures; one from rat cells and one from yeast cells
By applying Gene Set Enrichment Analysis (GSEA) we tested whether UPR genes tend to be differentially expressed in HD samples or models compared to the corresponding controls
Summary
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder. Its symptoms include loss of motor control, cognitive decline, and behavioural abnormalities. The outcome is always fatal with a life expectancy following the disease onset of around 20 years. The cause of HD is a mutation in a single gene called huntingtin (HTT). In HD patients, an expansion of the CAG repeat in exon 1 of huntingtin has been identified[1]. This mutation results in an extended stretch of polyglutamine close to the N-terminus of the Huntingtin protein (HTT), which is involved in multiple molecular functions[2,3]. Several studies have indicated that the unfolded protein response (UPR) might be implicated in neurodegenerative diseases including HD11–13
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