| Summary: | 碩士 === 國立臺灣師範大學 === 生命科學研究所 === 97 === Autosomal dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders involving progressive degeneration of the cerebellum, brainstem, and spinal tract. More than 28 subtypes have been reported. SCA17 is caused by an expanded polyglutamine (polyQ) in a general transcription initiation factor, the TATA-box binding protein (TBP). The mutated TBP with polyQ expansion causes a conformational change to promote misfolding and aggregation. Futhermore, a polyQ mutation can induce reactive oxygen species (ROS) that directly contribute to cell death. During oxidative stress, synthesis of several heat shock proteins (such as HSPA5, HSPA8 and HSPB1 chaperones) increase to protect cells against oxidative stress. Chaperones may modulate polyQ protein toxicity by stabilizing the misfolded conformation to reduce aggregate formation. Investigation of chaperones and oxidative stress associated with SCA17 may not only contribute to the understanding of molecular mechanism of the disease but also provide therapeutic strategy to slow down the disease progression. By establishing stably induced cell model, the study results revealed that TBP with expanded polyQ formed nuclear aggregates with significant increase in sub G1 phase of cell cycle. Cells expressed polyQ-expanded TBP display increased ROS production and increased sensitivity to staurosporine treatment and serum deprivation. Using transient cell model, HSPA5, HSPA8 and HSPB1 overexpression can reduce aggregate formation.
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