| Summary: | 碩士 === 國立成功大學 === 臨床醫學研究所 === 104 === 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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