Fig. 1: PolyQ toxicity in C. elegans is reduced upon AMP-activated protein kinase (AMPK) activation and requires lysosome function.

a Metformin was able to reduce aggregation in a dose-dependent manner in 1-day-old adult worms expressing 40Q::YFP in muscle cells. Treatment with metformin significantly rescued aggregates in a dose-dependent manner (p < 0.001). b Metformin required aak-2/AMPKα and lysosome function to reduce the number of inclusion bodies in L4 larvae. Larvae were used to test for AMPK function because the difference between mutant and wild-type worms is reduced as the animals age (data not shown). Treatment with metformin rescued aggregates in 40Q animals (p < 0.001). Chloroquine maintained high levels of inclusion bodies even when the 40Q worms are treated with metformin (p < 0.001). Metformin required aak-2/AMPK to partially rescue polyQ aggregation (p < 0.001). c Photographs of wild-type and aak-2/AMPKα mutant L4 larvae expressing 40Q::YFP in muscle cells treated with or without 2 mM metformin and/or 10 μM chloroquine. Larvae were used to test for AMPK function because the difference between mutant and wild-type worms is reduced as the animals age (data not shown). d Treatment with metformin significantly rescued neuronal function (assessed by the touch response; see Materials and methods) in 112Q-TdTomato worms (p < 0.001). The metformin-induced rescue of neuronal function required lysosomal function: chloroquine treatment reduced neuronal recovery even when the worms were treated with metformin (p = 0.261). e Worms require AMPKα activity to rescue the neuronal function induced by metformin. Metformin was applied to worms expressing 112Q-TdTomato in mechanosensory neurons in an aak-2 background. The touch response was assessed as above. Metformin required aak-2/AMPK to rescue neuronal function (p = 0.634). In all cases, values are the mean, and bars indicate the confidence interval (95% CI)