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Neuronal Calcium Channel Genes in Ataxia: "Safely Silencing a Sick Cistron"| old_uid | 14540 |
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| title | Neuronal Calcium Channel Genes in Ataxia: "Safely Silencing a Sick Cistron" |
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| start_date | 2017/10/27 |
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| schedule | 12h-13h |
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| online | no |
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| location_info | salle 01-02 |
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| details | Hosted by Alexis Brice |
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| summary | Neuronal Calcium Channel Genes in Ataxia: "Safely Silencing a Sick Cistron" We have discovered that the P/Q-type voltage-gated Ca2+ channel (VGCC) gene, CACNA1A, is a bicistronic cellular gene, i.e, encodes two structurally unrelated proteins, with distinct functions, that are separately encoded within the same mRNA. CACNA1A encodes both the ?1A (Cav2.1) subunit and a newly recognized transcription factor, ?1ACT, within an overlapping open reading frame (ORF) within the same mRNA transcript. This is achieved by the presence of a novel internal ribosomal entry site (IRES) upstream of a second ORF encoding ?1ACT. Although this is the first convincing evidence for a truly bicistronic gene in eukaryotes, there is evidence that other genes, including additional VGCC family genes, employ IRESs to encode separate gene regulatory proteins. Because complete elimination of ?1A expression is lethal, this IRES controlling ?1ACT is an excellent drugable target for therapies like miRNAs. To develop possible therapies we are studying small molecules, microRNAs and ASOs that preferentially suppress ?1ACT translation, but not ?1A subunit expression. Simultaneously, because this approach suppresses both the normal and expanded ?1ACT, we have used a doxycycline suppressible wild type ?1ACT transgene to show that ?1ACT is primarily important for early Purkinje cell maturation, and that its elimination in adults will not have adverse effects on cerebellar cortex function. |
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| responsibles | Oliviero |
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