Extended Data Fig. 8: LySR activation enhances aggregation clearance and extends healthspan.

a, qRT-PCR analysis (n = 4 biologically independent samples) of CL2122 and GMC101 worms cultured at two different temperatures since Larval 4 (L4) stage (****P < 0.0001; for cpr-5 at 20 °C, *P = 0.0174; for cpr-8 at 20 °C, ***P = 0.0001; for ctsa-1 at 20 °C, **P = 0.0054). b, Western blots of CL2122 or GMC101 worms treated with control (ev), vha-6_1 or vha-6_2 RNAi, cultured at two different temperatures since L4 stage. c, Chloroquine (CQ) treatment led to strong accumulation of amyloid-β aggregates and almost completely blunted vha-6 RNAi induced amyloid-β aggregation clearance. Western blots of GMC101 worms treated with control or vha-6 RNAi and treated with or without CQ at a final concentration of 1 mM or 5 mM. d, Survival of worms treated with control or vha-6 RNAi, and treated with or without CQ at 1 mM (left) or 5 mM (right) (****P < 0.0001, P = 0.8085 (N.S., vha-6 VS vha-6 + 1 mM CQ)). e,f, RNAi of vha-6 (20%) reduces disease-causing protein aggregate formation in unc-54p::Q35::YFP (Huntington’s disease polyQ model) (e) and unc-54p::Hsa-sod-1::YFP (ALS model) (f) worms. g, Worms expressing either unc-54p::Q35::YFP (polyQ model) (left) or unc-54p::Hsa-sod-1::YFP (ALS model) (right) were treated with control or vha-6 (20%) RNAi and/or 1-5 mM CQ, analyzed at Day 5 of adulthood. h, Paralysis (n = 10 independent worm plates for each condition) (left), or movement (n = 12 individual worms for each condition) (right) of worms as indicated in (e) and (f), respectively (****P < 0.0001). Scale bars, 0.3 mm. Error bars denote SEM. Statistical analysis was performed by two-tailed unpaired Student’s t-test (a), log-rank test (d), or ANOVA followed by Tukey post-hoc test (h) (N.S., not significant). Statistical data for lifespan can be found in Supplementary Table 1.

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