Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20226 (TATA-binding protein)
 1,297 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17. 2155 23

Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant neurodegenerative disease caused by CAG expansion in the gene encoding the TATA-binding protein (TBP). The neurological features of SCA17 are Purkinje cell loss and gliosis. We have generated SCA17 transgenic mice which recapitulate the patients' phenotypes and are suitable for the study of the SCA17 pathomechanism. Our previous study identified the activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) occurred in the SCA17 cerebella, this study aims to study the role of ERK activation in SCA17. The levels of pERK, calbindin, and gliosis markers on the mouse cerebellum at 4-8 weeks old were analyzed to elucidate the correlation among behavioral performance, ERK activation and Purkinje cell degeneration. The motor incoordination was initiated in SCA17 mice at 6 weeks old. We found that the presence of TBP nuclear aggregation and microglia activation were observed at 4 weeks old. Gliosis of astrocytes and Bergmann glia, pERK, Bax/Bcl2 ratio, and caspase-3 were significantly increased in the 6-week-old SCA17 mouse cerebellum. In addition to the polyglutamine-protein aggregation in Purkinje cells caused apoptosis cell-autonomously, a significant body of evidence have shown that ERK pathways involves in neuronal apoptosis. Our study showed that the activation of ERK in the astrocytes and Bergmann glia was identified as preceding motor deficits, which suggest the elevated gliosis by ERK activation may contribute to neuronal apoptosis in SCA17 mice.
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PMID:ERK activation precedes Purkinje cell loss in mice with Spinocerebellar ataxia type 17. 3287 10