亨丁頓舞蹈症是一個體染色體顯性遺傳的神經退化性疾病，目前臨床上無有效改善病程的藥物。亨丁頓舞蹈症的基因突變為4號染色體亨丁頓基因異常CAG序列異常的擴展，造成含聚谷氨酸鏈的突變亨丁頓蛋白。突變的亨丁頓蛋白可形成不可融且對神經有毒性的寡聚物、聚合物、集合體。神經毒性的機轉包括干擾基因轉錄、增加粒線體壓力以及降低蛋白酶體降解系統功能。熱休克效應可藉由將構型不正常的亨丁頓蛋白從型折疊而保護，並能減少突變亨丁頓蛋白形成集合體。PIN1蛋白使一個在神經細胞內含量豐富的正反異構酶並已知參與在多種細胞訊息傳遞中。我的研究結果顯示PIN1能藉由調控HSF1增加熱休克反應活性進而減少亨丁頓集合體。 在我的計畫中，我發現PIN1能和HSF1有交互作用，在HSF1的轉錄活性扮演重要的角色，並能增加熱休克蛋白的表現。在SHSY5Y及初級神經細胞中，PIN1在熱休克的環境下能降低亨丁頓包涵體及集合體的量。在PIN1基因剔除鼠的初級神經培養實驗中，PIN1的量和熱休克蛋白的表現量呈正向關係，並和集合體的量呈反向關係。在老鼠的動物實驗中，PIN1蛋白合併熱休克反應時能降低老鼠紋狀體內亨丁頓集合體的量，然而單獨調節PIN1蛋白並不足對集合體產生影響。我的發現顯示PIN1蛋白對於HSF1調控的亨丁頓集合體減少具有不可或缺的角色。

Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder with no current drug treatment that can effectively modify disease progression. The mutation that causes HD is an expansion of CAG repeats that codes for an abnormal polyglutamine (polyQ) tract in the huntingtin protein (Htt). Mutant Htt can form oligomers, polymers and large aggregates which are insoluble and toxic to neurons through interference with gene transcription, enhanced mitochondrial stress and dysfunction of the proteasome degradation system. Heat shock response (HSR) can protect cells from mutant Htt by refolding misfolded proteins and reducing the ability of mutant Htt to aggregate. PIN1 is an abudundant cis-trans isomerase in neurons that is known to participate in many cell signaling processes. In my project, I found that PIN1 can interact with HSF1, which is crucial for HSF1 tramsactivation and thus enhance key chaperon proteins expression attributed to HSR. Modulation PIN1 in SHSY5Y and cortical primary neuron under heat shock circumstances can interfere amount of aggregates and inclusion bodies. PIN1(+/+)、(+/-),(-/-) primary neuron result showed that PIN1 level is poositive correlated with chaperon protein expression and is negative related to aggregates level. In mouse model, I illustrate that PIN1 manipulation only has little effect on aggregates level, while PIN1 combined with HSF1 activation can decrease mutant Htt aggregates burden. My finding reveal that PIN1 is indispensable for HSF1-mediated Htt aggregates reduction.

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