<i>n</i>-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway
Spinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (<i>ATXN3</i>). The toxic fragments processed from mutant <i>ATXN3<...
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| author | Jui-Hao Lee Si-Yin Lin Jen-Wei Liu Shinn-Zong Lin Horng-Jyh Harn Tzyy-Wen Chiou |
| author_facet | Jui-Hao Lee Si-Yin Lin Jen-Wei Liu Shinn-Zong Lin Horng-Jyh Harn Tzyy-Wen Chiou |
| author_sort | Jui-Hao Lee |
| collection | DOAJ |
| description | Spinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (<i>ATXN3</i>). The toxic fragments processed from mutant <i>ATXN3</i> can induce neuronal death, leading to the muscular incoordination of the human body. Some treatment strategies of SCA3 are preferentially focused on depleting the abnormal aggregates, which led to the discovery of small molecule <i>n</i>-butylidenephthalide (<i>n</i>-BP). <i>n</i>-BP-promoted autophagy protected the loss of Purkinje cell in the cerebellum that regulates the network associated with motor functions. We report that the <i>n</i>-BP treatment may be effective in treating SCA3 disease. <i>n</i>-BP treatment led to the depletion of mutant <i>ATXN3</i> with the expanded polyQ chain and the toxic fragments resulting in increased metabolic activity and alleviated atrophy of SCA3 murine cerebellum. Furthermore, <i>n</i>-BP treated animal and HEK-293<i><sup>GFP-ATXN3-84Q</sup></i> cell models could consistently show the depletion of aggregates through mTOR inhibition. With its unique mechanism, the two autophagic inhibitors Bafilomycin A1 and wortmannin could halt the <i>n</i>-BP-induced elimination of aggregates. Collectively, <i>n</i>-BP shows promising results for the treatment of SCA3. |
| first_indexed | 2024-03-10T10:26:19Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:26:19Z |
| publishDate | 2021-06-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-68ba22fcd9d94e2884a597f01f5ad4782023-11-21T23:59:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012212633910.3390/ijms22126339<i>n</i>-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR PathwayJui-Hao Lee0Si-Yin Lin1Jen-Wei Liu2Shinn-Zong Lin3Horng-Jyh Harn4Tzyy-Wen Chiou5Everfront Biotech Inc., New Taipei City 22180, TaiwanEverfront Biotech Inc., New Taipei City 22180, TaiwanEverfront Biotech Inc., New Taipei City 22180, TaiwanBioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, TaiwanBioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien 97002, TaiwanDepartment of Life Science, Graduate Institute of Biotechnology, National Dong-Hwa University, Hualien 97447, TaiwanSpinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (<i>ATXN3</i>). The toxic fragments processed from mutant <i>ATXN3</i> can induce neuronal death, leading to the muscular incoordination of the human body. Some treatment strategies of SCA3 are preferentially focused on depleting the abnormal aggregates, which led to the discovery of small molecule <i>n</i>-butylidenephthalide (<i>n</i>-BP). <i>n</i>-BP-promoted autophagy protected the loss of Purkinje cell in the cerebellum that regulates the network associated with motor functions. We report that the <i>n</i>-BP treatment may be effective in treating SCA3 disease. <i>n</i>-BP treatment led to the depletion of mutant <i>ATXN3</i> with the expanded polyQ chain and the toxic fragments resulting in increased metabolic activity and alleviated atrophy of SCA3 murine cerebellum. Furthermore, <i>n</i>-BP treated animal and HEK-293<i><sup>GFP-ATXN3-84Q</sup></i> cell models could consistently show the depletion of aggregates through mTOR inhibition. With its unique mechanism, the two autophagic inhibitors Bafilomycin A1 and wortmannin could halt the <i>n</i>-BP-induced elimination of aggregates. Collectively, <i>n</i>-BP shows promising results for the treatment of SCA3.https://www.mdpi.com/1422-0067/22/12/6339MJDSCA3Purkinje cellPolyQatxain-3toxic fragment |
| spellingShingle | Jui-Hao Lee Si-Yin Lin Jen-Wei Liu Shinn-Zong Lin Horng-Jyh Harn Tzyy-Wen Chiou <i>n</i>-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway International Journal of Molecular Sciences MJD SCA3 Purkinje cell PolyQ atxain-3 toxic fragment |
| title | <i>n</i>-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway |
| title_full | <i>n</i>-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway |
| title_fullStr | <i>n</i>-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway |
| title_full_unstemmed | <i>n</i>-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway |
| title_short | <i>n</i>-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway |
| title_sort | i n i butylidenephthalide modulates autophagy to ameliorate neuropathological progress of spinocerebellar ataxia type 3 through mtor pathway |
| topic | MJD SCA3 Purkinje cell PolyQ atxain-3 toxic fragment |
| url | https://www.mdpi.com/1422-0067/22/12/6339 |
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