Generation of a neurodegenerative disease mouse model using lentiviral vectors carrying an enhanced synapsin I promoter
| Autor: | Miho Oue, Yasunori Matsuzaki, Hirokazu Hirai |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Genetically modified mouse
Synapsin I Transgene Genetic Vectors Green Fluorescent Proteins Ataxin 1 Mice Transgenic Nerve Tissue Proteins Viral vector Mice medicine Animals Humans Promoter Regions Genetic Gene Ataxin-1 Mice Inbred ICR biology General Neuroscience Lentivirus Gene Transfer Techniques Brain Nuclear Proteins Neurodegenerative Diseases Promoter Synapsins medicine.disease Molecular biology Rats Mice Inbred C57BL Disease Models Animal HEK293 Cells Ataxins biology.protein Spinocerebellar ataxia Decorin |
| Zdroj: | Journal of Neuroscience Methods. 223:133-143 |
| ISSN: | 0165-0270 |
| DOI: | 10.1016/j.jneumeth.2013.12.004 |
| Popis: | Background Certain inherited progressive neurodegenerative disorders, such as spinocerebellar ataxia (SCA), affect neurons in large areas of the central nervous system (CNS). The selective expression of disease-causing and therapeutic genes in susceptible regions and cell types is critical for the generation of animal models and development of gene therapies for these diseases. Previous studies have demonstrated the advantages of the short synapsin I (SynI) promoter (0.5 kb) as a neuron-specific promoter for robust transgene expression. However, the short SynI promoter has also shown some promoter activity in glia and a lack of transgene expression in significant areas of the CNS. New methods: To improve the SynI promoter, we used a SynI promoter that is twice as long (1.0 kb) as the short SynI promoter and incorporated a minimal CMV (minCMV) sequence. Results We observed that the 1.0 kb rat SynI promoter with minCMV [rSynI(1.0)-minCMV] exhibited robust promoter strength, excellent neuronal specificity and wide-ranging transgene expression throughout the CNS. Comparison with existing methods: Compared with the two previously reported short (0.5 kb) promoters, the new promoter was superior with respect to neuronal specificity and more efficiently transduced neurons. Moreover, transgenic mice expressing the mutant protein ATXN1[Q98], which causes SCA type 1 (SCA1), under the control of the rSynI(1.0)-minCMV promoter showed robust transgene expression specifically in neurons throughout the CNS and exhibited progressive ataxia. Conclusion rSynI(1.0)-minCMV drives robust and neuron-specific transgene expression throughout the CNS and is therefore useful for viral vector-mediated neuron-specific gene delivery and generation of neuron-specific transgenic animals. |
| Databáze: | OpenAIRE |
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