| 摘要: | 漢丁頓舞蹈症是一種神經退化疾病，致病原因是Huntingtin (Htt)基因上出現重覆且延長的 CAG 核酸序列。在腦部和其他周邊組織(例如: 肝臟)之中發現Htt突變蛋白塊形集結的情形，而引起了神經退化的產生。在漢丁頓舞蹈症中肝臟缺陷也是重要的特徵。我們之前己証實了失去調節的C/EBPα(對於維持能量恆定的轉錄因子)在漢丁頓舞蹈症中會引起尿素循環障礙，提供了對漢丁頓舞蹈症是可能的致病機轉。在這研究中我們將研究失調的C/EBPα和C/EBP α的下游轉錄因子PPARγ在漢丁頓舞蹈症的肝臟缺陷中所扮演角色。因此PPARγ的減少將是漢丁頓舞蹈症的病因。在R6/2老鼠（HD的小鼠模型）中給予0.01% thiazolidinedione [TZD; 過氧化小體增生活化受體 (PPARγ) 的活性劑]可以改善肝臟的尿素循環障礙、Htt突變蛋白塊形集結、危及的泛素化作用、受干擾的HSF1轉錄因子、內質網壓力和粒線體失調。在肝臟中 TZD經由減少Htt聚集而改善PPARγ被包入Htt的塊形集結，且TZD也可提升PPARγ的含量來增加PPARγ的兩個下游基因(例如: Bcl-2和PGC-1α)含量接近於正常值。以上的保護作用也在 HepG2細胞株中做測試，可經由PPARγ活化劑(rosiglitazone)來保護由Htt突變蛋白所引起的能量缺失和毒性。以上的觀察將支持漢丁頓舞蹈症中周邊組織的不正常是受到Htt突變蛋白的影響。這研究將可進一步探討PPARγ在漢丁頓氏舞蹈症中所扮演的角色，也將促使了解PPARγ 也許可以做為治療HD的標的物。本研究計畫的具體目標如下: Aim 1: 描述漢丁頓舞蹈症的肝臟缺陷 (8月1日, 2010 ~ 7月31日, 2011)。 Aim 2: 研究PPARγ減少Htt突變蛋白的機制 (8月1日, 2011 ~ 7月31日, 2012)。 Aim 3: 說明內質網和粒線體在漢丁頓舞蹈症的肝臟中所扮演角色 (8 月1 日, 2012 ~ 7 月 31 日, 2013)。
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The resultant mutant Htt protein (mHtt) forms aggregates in the brain and several peripheral tissues (e.g., the liver), and causes devastating neuronal degeneration. Liver defects resulting from Htt aggregates in peripheral abnormalities are important features of HD. We previously demonstrated that dysregulation of C/EBPα (a transcription factor vital for energy homeostasis) in HD causes urea cycle deficiency and significantly contributes to the pathology of HD. In the present study, we will report that dysfunction of C/EBPα and a downstream target [peroxisome proliferator-activated receptor-γ (PPARγ)] of C/EBPα showed in the livers of HD sufferers. Downregulation of PPARγ therefore is an authentic pathogenesis of HD. Regular treatment of well-characterized transgenic mouse model of HD (R6/2 mice) with an agonist (thiazolidinedione, TZD, 0.01%) of PPARγ resulted in an array of beneficial effects on urea cycle deficiency, formation of mHtt aggregates, jeopardized ubiquitination profiles, the hijacking of a crucial transcription factor (HSF1), ER stress, and mitochondrial dysfunction. By reducing Htt aggregates and therefore ameliorating the recruitment of PPARγ into Htt aggregates, regular TZD treatment also elevated the availability of PPARγ level and subsequently normalized the expression of two downstream genes (e.g., Bcl-2 and PGC-1α) of PPARγ in the liver. The above protective effects appeared to be exerted by a direct activation of PPARγ agonist (rosiglitazone) protected HepG2 cells from the mHtt-evoked energy deficiency and toxicity. The above observations will support the hypothesis that peripheral abnormalities in HD could be caused directly by local expression of mHtt. Based on preliminary results this will provide novel insights into the functions of PPARγ in HD, and might facilitate the concept that the PPARγ can be a potential therapeutic target in treating HD. Our specific aims are listed below: Aim 1: To delineate liver deficiency in HD (August 1, 2010 ~ July 31, 2011). Aim 2: To investigate the molecular mechanism underlying PPARγ’s action in modulating the formation of mHtt aggregates (August 1, 2011 ~ July 31, 2012). Aim 3: To elucidate the roles of ER and mitochondria in the liver of HD (August 1, 2012 ~ July 31, 2013). |
