Alleviation Of Proteotoxicity In Caenorhabditis Elegans Models Of Huntington’s Disease Via Modulating Proteostasis Networks

With an increasingly aging population, the late-onset neurodegenerative diseases have become one of the most common diseases all over the world. These diseases are characterized by progressive accumulation of aggregation-prone proteins and collapse of the proteostasis network. For example, Huntington’s disease (HD) is caused by abnormal polyglutamine (polyQ) aggregation and its proteotoxicity. Thus modulation of proteostasis and restoration of its imbalance are likely to be effective for diseases caused by protein misfolding and aggregation.Using C.elegans model, we test a set of compounds from Traditional Chinese Medicine, and we find that formula Kaixinsan and salidroside, a glycoside from Rhodiola rosea, are able to reduce neuronal death and behavioral dysfunction mediated by polyQ expression in the ASH neurons.We find that KXS can alleviate polyQ-mediated neuronal death and the associated chemosensory deficiency. KXS is also effective at reducing polyQ aggregation in vivo but not in vitro, indicating a complicated inhibitory mechanism. KXS modulates protein quality control systems by modulating the expression of heat shock proteins and by inducing autophagy to clear polyQ aggregates; KXS does not influence proteasome activity. KXS also reduces oxidative stress involved in proteostasis and neurodegeneration, but it does not influence aging stress or dietary restriction responses. These results suggest that KXS can alleviate polyQ-mediated neurotoxicity by regulating proteostasis networks in C. elegans.Salidroside is also effective against polyQ-mediated toxicity. The neuroprotective effect of salidroside is not associated with prevention of polyQ aggregation or aging. 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. Also, we find that salidroside can activate PMK-1/p38 signal pathway. These results demonstrate that salidroside exerts its neuroprotective function against polyQ toxicity via oxidative stress pathways and PMK-1/p38 pathway, two pathways involved in proteostasis network.All the results provide new insights into the therapeutic roles of modulation proteostasis networks in the prevention of proteotoxicity-related disorders in HD, and offer new active compounds for therapeutic treatment.