Abstract
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.
Highlights
Huntington’s disease (HD) is an age-related neurodegenerative disorder characterized by cognitive impairment and uncoordinated chorea, resulting from progressive loss of neuronal function [1]
We investigated the protective effect of salidroside on behavioral dysfunction in C. elegans models endogenously expressing polyQ, the key pathogenic protein leading to HD, and attempted to unravel the underlying mechanisms, including reduction of oxidative stress
When the nematodes were treated with 200 μM of salidroside, the neuronal survival rate increased to 41%, demonstrating that salidroside is capable fo reducing polyQ-mediated neuronal death
Summary
Huntington’s disease (HD) is an age-related neurodegenerative disorder characterized by cognitive impairment and uncoordinated chorea, resulting from progressive loss of neuronal function [1]. The genetic mutation responsible for HD is the redundant CAG repeats (≥36), which encode elongated polyglutamine (polyQ) tracts within the mutant huntingtin protein [2] It is well-known that polyQ and other pathogenic proteins (e.g., amyloid-β peptide; Aβ) associated with neurodegeneration often undergo conformational rearrangements and form insoluble aggregate deposits, which disrupt normal functions of neurons and cause damaging stresses such as transcription dysregulation, oxidative stress and ageing stress [3,4,5]. We investigated the protective effect of salidroside on behavioral dysfunction in C. elegans models endogenously expressing polyQ, the key pathogenic protein leading to HD, and attempted to unravel the underlying mechanisms, including reduction of oxidative stress
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