脊髓小腦運動失調症第十七型之微生物藥物篩檢模式：以 β-半乳糖苷酶結構互補特性偵測蛋白溶解度

郭欣嵐

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脊髓小腦運動失調症第十七型之微生物藥物篩檢模式：以 β-半乳糖苷酶結構互補特性偵測蛋白溶解度

Screening of Novel Molecules for SCA 17 Treatment by Using a Microbial Model: Monitoring Protein Solubility by β-Galactosidase Structural Complementation

郭欣嵐 , Masters　　Advisor：李冠群博士　　

繁體中文

第十七型脊髓小腦萎縮症； Spinocerebellar ataxia type 17

Abstract │ Reference (51) │ Altmetrics

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Many neurodegenerative diseases are linked to abnormally expanded CAG repeats in the coding regions of responsible genes. Spinocerebellar ataxia type 17 (SCA 17) was identified in CAG tri-nucleotide repeat expansion in the TATA-box binding protein (TBP) gene on chromosome 6q27. The possible molecular pathogenic mechanisms in SCA17 could be aggregation caused by mutant TBP with expanded polyglutamine (polyQ) strentches and dysfuction of transcriptional regulation by loss of function. An efficient cell-based screening for TBP aggregation inhibitors is important in drug discovery for SCA17 treatment. By structural complementation between the α- and ω-peptides of β-galactosidase (β-gal), the solubility of polyQ-expanded TBP can be monitored simply by the blue color of the culture and correlated with β-gal activity.In this study, we established an Escherichia coli. expression system to express the TBP/α fusion proteins. The results of phenotyping, genotyping, western blotting and β-gal activity assay showed that when α peptide was fused with insoluble polyQ-expanded TBP(Q40), it becomes misfolding and confer no β-gal activity. For this reason, the E. coli JM109(DE3) harboring pGEX-5x-3-fTBP(Q40)-lacZα can serve as a microbial model to screen for compounds that inhibit the polyQ-expanded TBP aggregation.
Using this model, we found that trehalose showed potency to inhibit polyQ-expanded TBP aggregation and can be used as a positive control. Therefore, in a plate assay format, this microbial model is suitable for rapidly screening novel compounds that are capable of inhibiting the aggregation of polyQ proteins.

Reference ( 51 ) 〈TOP〉

Barreca D, Laganà G, Ficarra S, Tellone E, Leuzzi U, Magazù S, Galtieri A and Bellocco E. Anti-aggregation properties of trehalose on heat-induced secondary structure and conformation changes of bovine serum albumin. Biophysical Chemistry 2010; 147(3): 146-152.
連結：
Belton PS and Gil AM. IR and Raman spectroscopic studies of the interaction of trehalose with hen egg white lysozyme. Biopolymers 1994; 34(7): 957-961.
連結：
Benaroudj N, Lee DH and Goldberg AL. Trehalose accumulation during cellular stress protects cells and cellular proteins from damage by oxygen radicals. The Journal of Biological Chemistry 2001; 276(26): 24261-24267.
連結：
Bence NF, Sampat RM and Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science 2001; 292(5521): 1552-1555.
連結：
Chai Y, Koppenhafer SL, Bonini NM and Paulson HL. Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. The Journal of Neuroscience 1999; 19(23): 10338-10347.
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