Kalathur Ravi Kiran Reddy, Giner-Lamia Joaquin, Machado Susana, Barata Tania, Ayasolla Kameshwar R S, Futschik Matthias E
Centre for Biomedical Research, University of Algarve, Faro, 8005-139, Portugal.
Centre for Biomedical Research, University of Algarve, Faro, 8005-139, Portugal; Centre of Marine Sciences, University of Algarve, Faro, 8005-139, Portugal.
F1000Res. 2015 May 1;4:103. doi: 10.12688/f1000research.6358.2. eCollection 2015.
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 53 genes, including RAB5A, HMGB1, CTNNB1, DNM1, TUBB, TSG101, EEF2, DYNC1H1, SLC12A5, ATG5, AKT1, CASP7 and SYVN1 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. Remarkably, we also found strong correlation of UPR gene expression with the length of the polyglutamine tract of Huntingtin, which is a critical determinant of age of disease onset in human HD patients pointing to the UPR as a promising target for therapeutic intervention. The study is complemented by a newly developed web-portal called UPR-HD (http://uprhd.sysbiolab.eu) that enables visualization and interactive analysis of UPR-associated gene expression across various HD models.
亨廷顿舞蹈病（HD）是一种进行性神经退行性疾病，最终会导致死亡。尽管致病基因（亨廷顿蛋白）已被发现20多年，但导致神经元细胞死亡的确切机制仍存在争议。HD患者大脑中观察到的神经元大量丧失的一个潜在机制可能是内质网（ER）中错误折叠蛋白积累激活的未折叠蛋白反应（UPR）。作为一种平衡未折叠或错误折叠蛋白积累的适应性反应，UPR上调伴侣蛋白的转录，暂时减弱新的翻译，并通过蛋白酶体激活蛋白降解。然而，持续的内质网应激和激活的UPR也会导致凋亡性细胞死亡。尽管不同研究表明UPR在HD中起作用，但证据仍不确凿。在此，我们进行了广泛的生物信息学分析，基于转录组数据揭示了不同实验性HD模型中的UPR激活。因此，我们鉴定出53个基因，包括RAB5A、HMGB1、CTNNB1、DNM1、TUBB、TSG101、EEF2、DYNC1H1、SLC12A5、ATG5、AKT1、CASP7和SYVN1，它们提供了UPR与HD之间的潜在联系。为了进一步阐明UPR作为与疾病相关过程的潜在作用，我们基于分子相互作用数据研究了它与凋亡的联系，并鉴定出一组40个基因，包括ADD1、HSP90B1、IKBKB、IKBKG、RPS3A和LMNB1，它们似乎处于这两个重要细胞过程的交叉点。值得注意的是，我们还发现UPR基因表达与亨廷顿蛋白的聚谷氨酰胺序列长度密切相关，聚谷氨酰胺序列长度是人类HD患者疾病发病年龄的关键决定因素，这表明UPR是一个有前景的治疗干预靶点。该研究得到了一个新开发的名为UPR-HD（http://uprhd.sysbiolab.eu）的网络门户的补充，该门户能够可视化和交互式分析各种HD模型中与UPR相关的基因表达。
