| Summary: | 博士 === 中山醫學大學 === 營養學系博士班 === 106 === Spinocerebellar ataxia type 3 (SCA3, also called Machado–Joseph disease (MJD), a late-onset and fatally inherited neurodegenerative disease, is caused by an abnormal expansion of the polyglutamine (polyQ) repeat in the protein ataxin-3. Until now, there is no established disease-modifying therapeutic strategy has been available for SCA3. Although the exact mechanism is unknown, the pathogenic effects of polyQ expanded mutant ataxin-3 protein are associated with not only misfolding and aggregation in nuclei of specific neurons but also dysregulation of transcription, protein degradation, mitochondrial function, apoptosis, and antioxidant potency and these thus trigger neuronal death. It is well established that phytochemicals in food through antioxidant and anti-apoptotic effects on neurons exert valuable therapeutic benefits in neurodegenerative diseases. Caffeic acid (CA), widely present in various agricultural products such as fruits, vegetables, wine, olive oil, and coffee, classified as a phenolic compounds of hydroxycinnamic acid and accounts for almost 90% of total phenolic acid intake in the diet. Resveratrol (Res), a polyphenolic stilbene, is present in variety of dietary sources such as red grapes, red wine, berries, nuts and peanuts. Although data have shown the antioxidant and antineurotoxic properties of CA and Res, the health effects of CA and Res against neurodegenerative progress in SCA3 is unknown. Here we investigated the protective role and possible mechanisms of CA and Res in SK-N-SH-MJD78 neuroblastoma cells and ELAV-SCA3tr-Q78 transgenic flies expressing mutant ataxin-3 and mutant ataxin-3 polyQ tract, respectively. Our data showed that CA and Res decreased apoptosis in the pro-oxidant tert-butyl hydroperoxide (tBH)-treated SK-N-SH-MJD78 cells. Moreover, treatments with CA and Res increased the levels of antioxidant and autophagy protein expression as well as diminished ROS, and expression and aggregation of mutant ataxin-3 in SK-N-SH-MJD78 cells. We further discovered that supplementations with CA and Res enhanced survival and motor performance in ELAV-SCA3tr-Q78 transgenic flies. CA and Res also diminished ROS, mutant ataxin-3 polyQ tract, and apoptotic-related molecules, as well as increased antioxidant and autophagy molecules in brain of ELAV-SCA3tr-Q78 transgenic flies. Notably, in SK-N-SH-MJD78 cells, using reporter gene assay, transfection experiments with a dominant-negative mutant IκB-α (DNM IκB-α) plasmid and Nrf2 siRNA demonstrated that the neuroprotective effects of CA and Res on SCA3 are through modulating transcriptional activity of p53, NF-κB and Nrf2. In summary, our findings demonstated the neuroprotective effect and possible mechanisms of CA and Res in improving mutant ataxin-3 induced ROS production and neuronal apoptosis. Moreover, these data could provide information for the preclinical studies of CA and Res in modulating neurodegenerative progression in SCA3.
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