Targeted stabilization of Munc18‐1 function via pharmacological chaperones

A–L

(A, C, E, G, I, K) Heat‐induced paralysis. Indicated worm strains maintained in compounds at indicated concentrations were exposed to 37 °C over a period of 120 min, and paralysis was scored at indicated time points. Data are means ± SEM (n = 3–4 independent experiments on ten worms per experiment; exact n and P values are shown in Appendix Table S1). (B, D, F, H, J, L) Quantification of paralysis at 20 min. Data are means ± SEM (*^,# P < 0.05, **^,## P < 0.01, ***^,### P < 0.001, ^# as compared to WT, * as compared to mutant by two‐way ANOVA and Dunnett’s multiple comparison test; n = 3–4 independent experiments on ten worms per experiment; exact n and P values are shown in Appendix Table S1).

M

Image of a worm, highlighting head and tail ganglia, as well as the ventral nerve cord and motor neurons.

N, O

Rescue of the subcellular localization of UNC‐18 in worms expressing G544D UNC‐18. C. elegans expressing WT::GFP or G544D::GFP at 1, 5, 20, or 100 µM compound were immobilized, and the ventral nerve cord was imaged. Solid arrowheads point to pairs of bigger puncta, broken arrowheads to single, smaller puncta (N, O). Scale bar in (N) and (O) = 10 µm. 4‐PBA = 4‐phenylbutyrate.

P

Quantification of soluble and aggregated UNC‐18. Data are means ± SEM (**P < 0.01, ***P < 0.001 by one‐way ANOVA and Dunnett’s multiple comparison test; n = 3–4 worms; exact n and P values are shown in Appendix Table S1).

Figure 8. Rescue of deficits in mutant C. elegans .