以SCA17小鼠小腦切片培養及基因轉殖鼠評估HDAC抑制劑對SCA17之效果

Abstract

脊髓小腦萎縮症第十七型 (SCA17) 是一種多麩胺酸造成的神經退化性疾病，是由於在TATA-box binding蛋白基因 (TBP基因) 上有不正常的CAG三核甘酸的擴增，造成TBP蛋白不正常摺疊並聚集在細胞當中，進而產生毒性。在SCA17的病徵上，目前有發現到有運動能力失調、運動功能障礙、認知功能失常等情形。TBP的主要功能是在細胞中啟動轉錄功能，組蛋白去乙醯化酶抑制劑 (HDACi) 可促使基因進行轉錄，因此被引用當作治療SCA17的藥物有其潛力。我們測試了多種HDACi化合物，當中發現LBH589可以在SCA17小腦組織培養上有效地降低TBP蛋白的聚集，然而在活體的實驗上發現LBH589不能有效改善SCA17運動失調的現象。此外，小鼠的食慾以及中樞神經系統發育可能會受到LBH589刺激而造成遲緩。因此，目前我們的活體實驗證據並無法說明LBH589對SCA17之治療是有幫助的。Spinocerebellar ataxia type 17 (SCA17) is a polyQ neurodegenerative disease caused by abnormal CAG repeat expansion of TATA-box binding protein (TBP) gene. The CAG trinucleotide expansion results in the mutant polyQ TBP protein misfolded and accumulated in the cells, which further caused the neuronal lose, especially the cerebellar Purkinje cells. Ataxia, motor dysfunction, and dementia are clinical symptoms of SCA17. As the role of TBP being critical in transcription initiation, improving the transcriptional activity by histone deacetylase inhibitors (HDACi) becomes an attractive approach for SCA17 treatment. We have screened several HDACi compounds and found that LBH589 could significantly reduce the TBP aggregation on SCA17 cerebellar slice culture. In in vivo study, we found LBH589 couldn’t ameliorate the motor function and the pathology of SCA17 mice. Additionally, the appetite of mice was reduced and the central nervous system was impacted by LBH589 treatment. We could not suggest that LBH589 is potential in SCA17 treatment from our in vivo results.