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Mutant polyQ-expanded ataxin-3 protein is prone to aggregation in affected neurons and is predominantly degraded by autophagy, which is beneficial for neurodegenerative disease treatment. Not only does mutant polyQ-expanded ataxin-3 increase susceptibility to oxidative cytotoxicity, but it also hampers antioxidant potency in neuronal cells. Nuclear factor erythroid-derived 2-like 2 (Nrf2), a master transcription factor that controls antioxidant and detoxification gene expression, plays a crucial role in neuroprotection in SCA3 and other neurodegenerative diseases. The present data showed that treatment with erinacine A-enriched Hericium erinaceus mycelium ethanol extract (HEME) extended longevity and improved locomotor activity in ELAV-SCA3tr-Q78 transgenic Drosophila. Moreover, HEME treatment enhanced antioxidant potency and autophagy, which, in turn, corrected levels of mutant polyQ-expanded ataxin-3 and restrained protein aggregation in both cell and Drosophila models of SCA3. Markedly, HEME increased the activation of Nrf2. Silencing Nrf2 protein expression negated most of the promising effects of HEME on SK-N-SH-MJD78 cells, highlighting the critical role of increased Nrf2 activation in the efficacy of HEME treatment. These findings suggest that HEME has therapeutic potential in SCA3 by enhancing autophagic and Nrf2-mediated antioxidant pathways, which may also influence neurodegenerative progression in other polyQ diseases.<\/jats:p>","DOI":"10.3390\/antiox13121495","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T04:01:37Z","timestamp":1733716897000},"page":"1495","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Erinacine A-Enriched Hericium erinaceus Mycelium Ethanol Extract Lessens Cellular Damage in Cell and Drosophila Models of Spinocerebellar Ataxia Type 3 by Improvement of Nrf2 Activation"],"prefix":"10.3390","volume":"13","author":[{"given":"Yu-Ling","family":"Wu","sequence":"first","affiliation":[{"name":"Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Lun","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Pediatrics, Division of Allergy, Asthma and Rheumatology, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jui-Chih","family":"Chang","sequence":"additional","affiliation":[{"name":"Center of Regenerative Medicine and Tissue Repair, Changhua Christian Hospital, Changhua 500, Taiwan"},{"name":"General Research Laboratory of Research Department, Changhua Christian Hospital, Changhua 500, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8443-6180","authenticated-orcid":false,"given":"Wei-Yong","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan"},{"name":"Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Yin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Senior Citizen Welfare and Long-Term Care Business (Master Program), Hungkuang University, Taichung 433, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Chu","family":"Chen","sequence":"additional","affiliation":[{"name":"Biotech Research Institute, Grape King Bio Ltd., Taoyuan 325, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Ya","family":"Lee","sequence":"additional","affiliation":[{"name":"Biotech Research Institute, Grape King Bio Ltd., Taoyuan 325, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Chun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Nutrition, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingli","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Life Science and Life Science Research Center, Tunghai University, Taichung 407, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7611-5515","authenticated-orcid":false,"given":"Haw-Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nutrition, China Medical University, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Chen","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-9654","authenticated-orcid":false,"given":"Chin-San","family":"Liu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan"},{"name":"Vascular and Genomic Center, Institute of ATP, Changhua Christian Hospital, Changhua 50094, Taiwan"},{"name":"Department of Neurology, Changhua Christian Hospital, Changhua 500, Taiwan"},{"name":"Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Li","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Nutrition, Chung Shan Medical University Hospital, Taichung 402, 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