Therapeutic evaluation of granulocyte colony-stimulating factor on SCA17 transgenic mice

• Main Authors: Ya-Chin Chang, 張雅津
• Other Authors: Hsiu-Mei Hsieh,Ph.D.
• Format: Others
• Language: zh-TW
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/90829577564732332057

博士 === 國立臺灣師範大學 === 生命科學研究所 === 99 === SCA17 is an autosomal dominant cerebellar ataxia (ADCA) caused by the polyglutamine (polyQ) expansion of transcription factor TATA binding protein (TBP). The length of polyQ tract encoded by the CAA/CAG repeats of TBP gene is related to the disease severity. The range of CAG repeats is 25-42 in normal population and 47-55 in SCA17 patients. We speculated that TBP trinucleotide expansion might disrupt comformation of protein folding and lead to cell death. To investigate the TBP trinucleotide expansion effect on neurodegeneration, our previous studies have generated transgenic (TG) mice expressing the human TBP (hTBP) gene with expanded 109 CAA/CAG tracts under the control of Purkinje cell-specific promoter, Pcp2/L7 promoter. These TG mice showed ataxia and reduced rotarod latency compared to their wild-type (WT) littermates. Immunohistochemical analysis has shown that the Purkinje cells in transgenic mouse cerebellum were lost severely. Furthermore, we confirmed that hTBP109Q TG mice had calbindin, inositol 1,4,5-triphosphate receptor 1 (Itpr1) and Cacna1g downregulated by both cDNA microarray and Western blot analysis. This result suggests that transgene expression in the mouse brain might result in the impairment of calcium homeostasis, which may in turn causes the neuron degeneration and ataxia. Reactive gliosis and neuroinflammation were also occurred in the TG mouse cerebellum showing the upregulation of GFAP and Iba1. The hTBP TG disease model recapitulates the phenotypes of SCA17 patients. This model could help us to gain more insight about the molecular pathogenesis and can be used as a platform for drug testing. We thus applied G-CSF on these mice to identify whether it could ameliorate the phenotypes of TG mice. Our results showed that G-CSF treatment at post-symptomatic stage could activate p-ERK survival pathway and showed neuroprotective effect on SCA17 transgenic mice. Compared to the late stage treatment, the G-CSF treatment at the pre-symptomatic stage showed increasing of Hsp70 expression level, which could retard the phenotype on the pathology and behavior of transgenic mice and result in a neuroprotective effect. G-CSF treatment of SCA17 mice also increased LC3-II/Actin ratio which suggested an increasing autophagy activity and enhanced the clearance of SCA17 protein. We conclude that at both the pre-symptomatic or post-symptomatic stages, G-CSF has neuroprotective effect on SCA17 mice. G-CSF may be a potential therapeutic drug for the treatment of SCA17 disease.