新奇基因 BC1在 Huntingtin 所引起的蛋白質聚集及細胞毒性上的研究

Abstract

我們研究室在 GCH ( GTP cyclohydrogenase I）的 Hela dominant negative 細胞模型中分離出來的一個新的基因（ BC1）。 BC1在不具有 dominant negative 機制的細胞中表現較多，而且能幫助 GCH 聚合體蛋白組合成穩定的結構。故 BC1可能參與了細胞內蛋白質的折疊和分解的機制。近來一些研究報導指出許多蛋白質像是 amy1oid, tau ，-synuclein and polyglutamine containing proteins 的聚集和不正常的折疊都與遺傳性神經退化疾病有關。因此我們探討 BC1對於其中的一種神經退化疾病一漢丁頓氏舞蹈症的影響。 神經細胞死亡和細胞內有蛋白質聚集，是漢丁頓氏舞蹈症的特徵。突變 Huntingtin 蛋白質的 N 端片段就是造成蛋白質聚集和神經細胞死亡的元兇。在我們的研究中，我們發現 BC1能避免 polyQ－Huntingtin 所引起的蛋白質聚集和神經細胞死亡，此外 BC1 與 Huntingtin 更有些微的交互作用，而BC1在細胞內的分子作用機制則需要再進一步的研究。

A novel gene, BC1, was isolated from the GCH (GTP cyclohydrogenase I) Dominant negative cell models. BC1 expressed mainly in the non-DN cells, and had effect on stabilizing polymeric GCH proteins. It seems that BC1 may be involved in folding and degradation pathway. There are many neurodegenerative diseases involved aggregation and deposition of misfolded proteins such as amyloid β, tau , α-synuclein and polyglutamine containing proteins been reported. We investigate that if BC1 may have effect on misfolded protein induced neurodegenerative disease. Neuronal loss and intraneuronal protein aggregates are characteristics of Huntington’s disease (HD), caused by an expanded polyglutamine [polyQ] tract in the disease protein. N-terminal fragments of mutant huntingtin produce intracellular aggregates and cause toxicity. In this study, we found that BC1 can inhibit polyQ-Htt induced aggregation, have moderate interaction with Htt, and may suppress polyQ-Htt induced cell toxicity.