Key result
Genetic deletion of PKCα and PKCβ in a mouse model of RNA toxicity did not alter disease progression, muscle histopathology, or CELF1 expression, indicating these phenotypes are independent of PKCα and PKCβ.
Why the study?
Does genetic deletion of PKCα and PKCβ improve disease phenotypes in a mouse model of RNA toxicity?
Does genetic deletion of PKCα and PKCβ improve disease phenotypes in a mouse model of RNA toxicity?
Genetic deletion of PKCα and PKCβ does not rescue disease phenotypes or reduce CELF1 expression in a mouse model of RNA toxicity, suggesting these kinases are not the primary drivers of CELF1 stabilization in this model.
Answers are grounded in this paper and cite their sources.
PKCα/β deletion fails to rescue RNA toxicity phenotypes in mice; leaves open other drivers of CELF1 expression and cautions against these kinases as targets.
Myotonic dystrophy type 1(DM1) is the prototype for diseases caused by RNA toxicity. RNAs from the mutant allele contain an expanded (CUG)n tract within the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The toxic RNAs affect the function of RNA binding proteins leading to sequestration of muscleblind-like (MBNL) proteins and increased levels of CELF1 (CUGBP, Elav-like family member 1). The mechanism for increased CELF1 is not very clear. One favored proposition is hyper-phosphorylation of CELF1 by Protein Kinase C alpha (PKCα) leading to increased CELF1 stability. However, most of the evidence supporting a role for PKC-α relies on pharmacological inhibition of PKC. To further investigate the role of PKCs in the pathogenesis of RNA toxicity, we generated transgenic mice with RNA toxicity that lacked both the PKCα and PKCβ isoforms. We find that these mice show similar disease progression as mice wildtype for the PKC isoforms. Additionally, the expression of CELF1 is also not affected by deficiency of PKCα and PKCβ in these RNA toxicity mice. These data suggest that disease phenotypes of these RNA toxicity mice are independent of PKCα and PKCβ.
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Kim et al. (2016) studied Myotonic dystrophy type 1 (DM1) / RNA toxicity. Genetic deletion of PKCα and PKCβ vs. Wildtype PKCα and PKCβ was evaluated on Disease phenotypes including myotonia, muscle histopathology, CELF1 expression, and RNA splicing defects. Genetic deletion of PKCα and PKCβ in a mouse model of RNA toxicity did not alter disease progression, muscle histopathology, or CELF1 expression, indicating these phenotypes are independent of PKCα and PKCβ.
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