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[P88]: Establishment of the SCA17 pathogenic model in C. elegans for gene therapy and pharmaceuticals screening
Author(s) -
Pai C.K.,
LeeChen G.J.,
Su M.T.,
Li M.L.
Publication year - 2006
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2006.09.151
Subject(s) - library science , chen , citation , political science , computer science , biology , paleontology
Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant cerebellar ataxia caused by abnormal expansion of a CAG/CAA repeat encoding a polyglutamine (polyQ) tract in the TATA binding protein (TBP) gene. The TBP is an important general transcription initiation factor and is the DNA-binding subunit of RNA polymerase II transcription factor D (TFIID). (CAG)n polymorphism of human TBP are 25Q–42Q repeats for normal range, 43Q–46Q repeats for intermediate size and 47Q–63Q for abnormal size. Existence of polyQ tract of TBP in animals may lead to cell death and neurodegeneration. For this disease, we hope to investigate the feasibility of gene therapy with RNAi and to establish a large-scale drugs screening test in a C. elegans disease model. We first constructed expressed human TBP with 36Q and 61Q plasmids under the motor neuron specific expressed acr-2 promoter of C. elegans. By microinjection of these vectors into wild-type (N2) C. elegans, we had obtained several transgenic SCA17 disease lines. Their hatch rate, lifespan, creep speed and motion amplitude were significantly decreased with the polyQ expanding as compared to wild-type worms. These results clearly showed that the polyQ expanded TBP is toxic to C. elegans and transgenic SCA17 worm is suitable served as a disease model for therapeutic testing purpose. We further used RNAi to specifically knockdown human TBP gene for SCA17 C. elegans rescuing experiment; and found that RNAi treatment can improve the hatch rate and delay the appearance of motion ataxia. Such results suggested that RNAi can be a potential method for SCA17 gene therapy. In the future, we also plan to use the C. elegans model to screen other effective new drugs for SCA17.