Fig. 6.

Genetic and pharmacological suppression of muscle defects caused by mutant Lamin C. (A) Graph of the percentage of live adults produced from crosses between flies expressing mutant LamC (G489V) via the C57 larval muscle-specific Gal4 driver and a stock possessing either a Gal4-activated RNAi or an over-expressed transgene as indicated. Expression of mutant LamC (no RNAi) caused death at the pupal stage with no surviving adults. Expression of a non-specific luciferase RNAi (neg. control) allowed survival of only a few adults. By contrast, partial suppression of lethality was observed for the RNAi and over-expression transgenes. Approximately 200–300 total progeny were scored per genotype. Unpaired Student's t-tests were performed for statistical analysis. θ = no survivors. (B) The percent of viable adults after treatment with either 5 mM pamoic acid or vehicle (dH₂0) only was plotted. Viability was calculated as described for (A). Pamoic acid treatment had no effect on the viability of flies expressing wild-type LamC. By contrast, treatment increased the survival of flies expressing mutant LamC. Unpaired Student's t-tests were performed for statistical analysis. (C) A model illustrating a self-perpetuating cycle that is initiated by cytoplasmic aggregation of nuclear envelope proteins, leads to the activation of the Nrf2/Keap1 pathway, resulting in reductive stress, which promotes cytoplasmic aggregation. The reductive environment promotes additional protein aggregation, causing the cycle to repeat. Red arrows indicate suppression via RNAi, and green arrows indicate overexpression. *, p < 0.05; ***, p < 0.001. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)