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The inherited polyglutamine (polyQ) expansion diseases are characterized by progressive accumulation of aggregation-prone polyQ proteins, which may provoke proteostasis imbalance and result in significant neurotoxicity. Using polyQ transgenic Caenorhabditis elegans models, we find that Kai-Xin-San (KXS), a well-known herbal formula traditionally used to treat mental disorders in China, can alleviate polyQ-mediated neuronal death and associated chemosensory deficiency. Intriguingly, KXS does not reduce polyQ aggregation in vitro as demonstrated by Thioflavin-T test, but does inhibit polyQ aggregation in C. elegans models, indicating an indirect aggregation-inhibitory mechanism. Further investigation reveals that KXS can modulate two key arms of the protein quality control system, that is, heat shock response and autophagy, to clear polyQ aggregates, but has little effect on proteasome activity. In addition, KXS is able to reduce oxidative stress, which is involved in proteostasis and neurodegeneration, but has no effect on life span or dietary restriction response. To examine potential interaction of the four component herbs of KXS, a dissection strategy was used to study the effects of differential herbal combinations in C. elegans polyQ models. While the four herbs do contribute additively to KXS function, Panax ginseng is found to be the most effective constituent. Taken together, these findings not only demonstrate the neuroprotective ability of KXS but also suggest its potential as a proteostasis regulator in protein aggregation disorders and provide an insight into the mechanism studies of traditionally used complex prescriptions and their rationality.

Epimedium has been traditionally used to treat a variety of medical conditions, including neurological disorders. In this study, an acidic polysaccharide EbPS-A1 is isolated from Epimedium brevicornum and found to contain mainly galacturonic acid, galactose, and rhamnose but also arabinose and glucuronic acid. Using Caenorhabditis elegans models, we show that EbPS-A1 is capable of inhibiting behavioral dysfunction mediated by polyglutamine (polyQ), which is implicated in several neurodegenerative disorders such as Huntington's disease. Interestingly, EbPS-A1 does not inhibit polyQ aggregation or extend lifespan in the nematodes; it does, however, improve the survival under increased oxidative stress of both polyQ and wild-type nematodes intoxicated by paraquat. Further studies reveal that EbPS-A1 is capable of not only scavenging free radicals in vitro but also reducing reactive oxygen species levels, enhancing antioxidant enzyme activities, and decreasing lipid peroxidation product in C. elegans models. Together, these results suggest that the protective effect of Epimedium polysaccharide against polyQ-mediated neurotoxicity is likely due to its antioxidant function.

Polyglutamine (polyQ) aggregation plays a pivotal role in the pathological process of Huntington's disease and other polyQ disorders. Therefore, strategies aiming at restoring dysfunction and reducing stresses mediated by polyQ toxicity are of therapeutic interest for proteotoxicity diseases. Salidroside, a glycoside from Rhodiola rosea, has been shown to have a variety of bioactivities, including antioxidant activity. Using transgenic Caenorhabditis elegans models, we show here that salidroside is able to reduce neuronal death and behavioral dysfunction mediated by polyQ expressed in ASH neurons, but the neuroprotective effect is not associated with prevention of polyQ aggregation per se. Further experiments reveal that the neuroprotective effect of salidroside in C. elegans models involves its antioxidant capabilities, including decrease of ROS levels and paraquat-induced mortality, increase of antioxidant enzyme activities and reduction of lipid peroxidation. These results demonstrate that salidroside exerts its neuroprotective function against polyQ toxicity via oxidative stress pathways.

Late-onset neurodegenerative diseases are characterized by progressive accumulation of aggregation-prone proteins and global disruption of the proteostasis network, e.g. abnormal polyQ (polyglutamine) aggregation in Huntington's disease. Astragalus membranaceus polysaccharide (astragalan) has recently been shown to modulate aging and proteotoxic stress pathways. Using Caenorhabditis elegans models, we now show that astragalan not only reduces polyQ aggregation, but also alleviates the associated neurotoxicity. We also reveal that astragalan can extend the adult lifespan of wild-type and polyQ nematodes, indicating a connection of its anti-aging benefit with the toxicity-suppressing effect. Further examination demonstrates that astragalan can extend the lifespan of daf-2 and age-1, but not daf-16, mutant nematodes of the insulin-like aging and stress pathway, suggesting a lifespan-regulation signalling independent of DAF (abnormal dauer formation)-2/IGF-1R (insulin-like growth factor 1 receptor), but dependent on the DAF-16/FOXO (forkhead box O) transcription factor, a pivotal integrator of divergent signalling pathways related to both lifespan regulation and stress resistance. We also show that a subset of DAF-16 downstream genes are regulated by astragalan, including the DAF-16 transcriptional target gene scl-20, which is itself constitutively up-regulated in transgenic polyQ nematodes. These findings, together with our previous work on LEA (late embryogenesis abundant) proteins and trehalose, provide a revealing insight into the potential of stress and lifespan regulators in the prevention of proteotoxic disorders.