title: Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17.
abstract: Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant inherited disorder characterized by degeneration of spinocerebellar tracts and selected brainstem neurons owing to the expansion of a CAG repeat of the human TATA-binding protein (hTBP) gene. To gain insight into the pathogenesis of this hTBP mutation, we generated transgenic mice with the mutant hTBP gene driven by the Purkinje specific protein (Pcp2/L7) gene promoter. Mice with the expanded hTBP allele developed ataxia within 2-5 months. Behavioral analysis of L7-hTBP transgenic mice showed reduced fall latency in a rotarod assay. Purkinje cell degeneration was identified by immunostaining of calbindin and IP3R1. Reactive gliosis and neuroinflammation occurred in the transgenic cerebellum, accompanied by up-regulation of GFAP and Iba1. The L7-hTBP transgenic mice were thus confirmed to recapitulate the SCA17 phenotype and were used as a disease model to explore the potential of granulocyte-colony stimulating factor in SCA17 treatment. Our results suggest that granulocyte-colony stimulating factor has a neuroprotective effect in these transgenic mice, ameliorating their neurological and behavioral deficits. These data indicate that the expression of the mutant hTBP in Purkinje cells is sufficient to produce cell degeneration and an ataxia phenotype, and constitutes a good model for better analysis of the neurodegeneration in SCA17.
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Ya-Chin
authors.initials: YC
authors.lastname: Chang
authors.forename: Cheng-Yueh
authors.initials: CY
authors.lastname: Lin
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Hsu
authors.forename: Hsin-Chieh
authors.initials: HC
authors.lastname: Lin
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
authors.forename: Ming-Tsan
authors.initials: MT
authors.lastname: Su
authors.forename: Long-Sun
authors.initials: LS
authors.lastname: Ro
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
authors.forename: Hsiu Mei
authors.initials: HM
authors.lastname: Hsieh-Li
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010641:Phenotype; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D035181:TATA-Box Binding Protein / Q000235:genetics* / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D035181:TATA-Box Binding Protein; C509817:TBP protein, human; D016179:Granulocyte Colony-Stimulating Factor