헌팅턴씨병 치료를 위한 단백질 응축현상을 억제하는 접근방법 연구
- 헌팅턴씨병 치료를 위한 단백질 응축현상을 억제하는 접근방법 연구
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- Huntington’s disease (HD) is a late-onset and progressive neurodegenerative disorder that is caused by aggregation of mutant huntingtin (mHtt) protein which contains expanded-polyglutamine. Aggregation of mHtt induces a number of neuronal protein sequestration by aberrant interaction. Accordingly, depletion of transcriptional factor and molecular motor cause the transcriptional dysregulation of important neuronal genes such as BDNF, neurotransmitters and its cognate receptors, and axonal transport of vesicles and mitochondria, leading to neurodegeneration. According to our understating of the pathogenesis, it would be rational therapeutic approach to treat HD through inhibition of mHtt aggregation, followed by subsequent alleviation of its downstream harmful effects. Molecular chaperones may have a central role in this process, and anti-aggregation drugs are also shed the light in this approach. Here, I focus on the molecular mechanism of eukaryotic chaperonin TRiC/CCT degradation and development of delivery system of anti-aggregation drugs such as trehalose.Recently, the eukaryotic chaperonin TRiC/CCT has been shown to play an important role in protecting cells against the accumulation of misfolded polyglutamine protein aggregates. It is essential to elucidate how TRiC/CCT function is regulated to better understand the pathological mechanism of polyglutamine aggregation. VRK2 is a member of the novel serine/threonine kinase family, but its function has remained unexplored. Here, I propose that VRK2 is a critical enzyme that negatively regulates TRiC/CCT. VRK2 decreased endogenous TRiC/CCT levels by promoting its ubiquitination dependent on kinase activity. Interestingly, VRK2 increased aggregate formation of polyglutamine-expanded huntingtin fragment. This effect requires recruitment of COP1 E3 ligase. In addition, USP25 was determined as a deubiquitinating enzyme for TRiC and activity of USP25 was suppressed by VRK2-mediated phosphorylation. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC/CCT which controls folding of polyglutamine proteins involved in Huntington’s disease.Many attempts were made to inhibit the polyglutamine-induced protein aggregation, and the non-reducing disaccharide trehalose was reported to alleviate the disease symptoms of HD transgenic mice. However, trehalose is known to be rapidly hydrolysed to glucose by trehalase enzyme present in the small intestine, and its uptake into tissues is regarded to be very low. In addition, there is no evidence that trehalose can cross the blood-brain barrier (BBB) and enter the mammalian brain. Here I show that BBB-permeable trehalose derivatives could be prepared by applying the delivery methods using guanidine residue, and the derivatives were found to efficiently prevent the aggregation of polyQ in the transfected HEK293 cells. Furthermore, the derivative (TD-G6), when given ad libitum to a transgenic mouse model of HD (Tg R6/2), was found to significantly prolong lifespan, improve motor functions and reduce the inclusion bodies in the mouse brain compared with the trehalose control. These data strongly suggest that the BBB-permeable trehalose derivative may be used as a potential therapeutic agent for HD, and that further refinement of the present delivery technology might have significant potential applications for the treatment of many other intractable degenerative neurological diseases.
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