| Summary: | 碩士 === 國立臺灣師範大學 === 生命科學研究所 === 98 === Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is the most common autosomal dominant inherited ataxia. SCA3 is caused by a CAG trinucleotide expansion in the MJD1 gene, which is located on chromosome 14q24.3-q31, and translated into a polyglutamine (polyQ) stretch containing ataxin-3 (AT3) protein. Expansion of the glutamine domain in AT3, as well as in eight other members of polyQ neurodegenerative disease family, increases protein misfolding, results in aggregation and formation of nuclear and cytoplasmic inclusions. Inclusions of polyQ proteins are ubiquitylated and contain proteasomes, suggesting an attempt by the ubiquitin proteasome system (UPS) to degrade the misfolded protein. However, little is known about the correlation between aggregate formation and cell death. To further study the role of AT3 in SCA3 neuropathology, we have established AT3-inducible PC12 cells. This cell model should allow us to characterize the aggregation of full-length AT3 protein in living cells. Our results showed that AT3 mutant protein (75Q) expression in the PC12 cells intend to cause the formation of the nuclear or peri-nuclear aggregation. Futhermore, cell survival declined with the expression of extended polyQ AT3, especially under differentiated condition induced by NGF treatment. In addition, we found that neurotoxicity of expanded AT3 (Q75) could further cause unhealthy morphology and high sensitivity to oxidative stress. With this cell model, we have evaluated the neuron protective effect of several histone deacetylase (HDAC) inhibitors and antioxidant compounds. All of these HDAC inhibitors could sustain cell viability significantly when cells were treated with low dosage of these compounds. These results suggest that regulation of gene expression is involved in the neuropathology of SCA3. In conclusion, we have established an SCA3 inducible cell model which could be used as a platform for screening of potential therapeutic strategies for SCA3 and other polyQ-mediated neurodegenerative diseases.
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