Abstract
AbstractHuntington's disease (HD) is a progressive, neurodegenerative disease with fatal outcome. Although the disease-causing gene (huntingtin) has been known for some time, the exact cause of neuronal cell death is still unknown. One potential mechanism contributing to the massive loss of neurons in the brain of HD patients might be the unfolded protein response (UPR), which is activated by accumulation of misfolded proteins in the endoplasmatic 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, it is known that persistent ER stress and activated UPR can cause cell death by triggering of apoptosis. Nevertheless, the evidence linking UPR with HD progression remains inconclusive. Here, we present first analyses of UPR activation during HD based on available expression data. To elucidate the potential role of UPR as a disease-relevant process, we examine its connection to cell death and inflammatory processes. Due to the complexity of these molecular mechanisms, a systems biology approach was pursued.
Highlights
Its symptoms are loss of motor control, cognitive decline, endoplasmatic reticulum (ER) exceeded its capacity for correct folding
Cells could possibly lead to axonal damage and extensive recently, studies have indicated that the ER stress and unfolded protein response (UPR) neuronal cell death in Huntingtons disease (HD) pathology [6,7,8,9]
Different mechanisms triggered by ER stress in the context of HD can be found in figure1
Summary
Ravi Kiran Reddy Kalathur, Kameshwar Ayasolla and Matthias E. One potential mechanism contributing to the massive loss of neurons in the brain of HD patients might be the unfolded protein response (UPR), which is activated by accumulation of misfolded proteins in the endoplasmatic 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. It is known that persistent ER stress and activated UPR can cause cell death by triggering of apoptosis. The molecular cause has chaperones, persistent ER stress can mediate toxicity and been known for almost 20 years, the exact mechanisms eventually lead to apoptosis through activation of JNK, leading to the observed massive cell death of neurons in the ASK1 and caspase-12. Different mechanisms triggered by ER stress in the context of HD can be found in figure
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