Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction
TAR DNA-binding protein 43 (TDP-43) is a member of an evolutionarily conserved family of heterogeneous nuclear ribonucleoproteins that modulate multiple steps in RNA metabolic processes. Cytoplasmic aggregation of TDP-43 in affected neurons is a pathological hallmark of many neurodegenerative diseas...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/1/82 |
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| author | Yu-Mi Jeon Younghwi Kwon Shinrye Lee Seyeon Kim Myungjin Jo Seongsoo Lee Sang Ryong Kim Kiyoung Kim Hyung-Jun Kim |
| author_facet | Yu-Mi Jeon Younghwi Kwon Shinrye Lee Seyeon Kim Myungjin Jo Seongsoo Lee Sang Ryong Kim Kiyoung Kim Hyung-Jun Kim |
| author_sort | Yu-Mi Jeon |
| collection | DOAJ |
| description | TAR DNA-binding protein 43 (TDP-43) is a member of an evolutionarily conserved family of heterogeneous nuclear ribonucleoproteins that modulate multiple steps in RNA metabolic processes. Cytoplasmic aggregation of TDP-43 in affected neurons is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Mislocalized and accumulated TDP-43 in the cytoplasm induces mitochondrial dysfunction and reactive oxidative species (ROS) production. Here, we show that TDP-43- and rotenone-induced neurotoxicity in the human neuronal cell line SH-SY5Y were attenuated by hydroxocobalamin (Hb, vitamin B<sub>12</sub> analog) treatment. Although Hb did not affect the cytoplasmic accumulation of TDP-43, Hb attenuated TDP-43-induced toxicity by reducing oxidative stress and mitochondrial dysfunction. Moreover, a shortened lifespan and motility defects in TDP-43-expressing <i>Drosophila</i> were significantly mitigated by dietary treatment with hydroxocobalamin. Taken together, these findings suggest that oral intake of hydroxocobalamin may be a potential therapeutic intervention for TDP-43-associated proteinopathies. |
| first_indexed | 2024-03-10T03:00:56Z |
| format | Article |
| id | doaj.art-91e62b4a06b94d0daae5e7ee31caa6d2 |
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| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T03:00:56Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-91e62b4a06b94d0daae5e7ee31caa6d22023-11-23T12:47:02ZengMDPI AGAntioxidants2076-39212021-12-011118210.3390/antiox11010082Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial DysfunctionYu-Mi Jeon0Younghwi Kwon1Shinrye Lee2Seyeon Kim3Myungjin Jo4Seongsoo Lee5Sang Ryong Kim6Kiyoung Kim7Hyung-Jun Kim8Dementia Research Group, Korea Brain Research Institute, Daegu 41068, KoreaDementia Research Group, Korea Brain Research Institute, Daegu 41068, KoreaDementia Research Group, Korea Brain Research Institute, Daegu 41068, KoreaDementia Research Group, Korea Brain Research Institute, Daegu 41068, KoreaDementia Research Group, Korea Brain Research Institute, Daegu 41068, KoreaGwangju Center, Korea Basic Science Institute, Gwangju 61886, KoreaSchool of Life Sciences, Kyungpook National University, Daegu 41566, KoreaDepartment of Medical Biotechnology, Soonchunhyang University, Asan 31538, KoreaDementia Research Group, Korea Brain Research Institute, Daegu 41068, KoreaTAR DNA-binding protein 43 (TDP-43) is a member of an evolutionarily conserved family of heterogeneous nuclear ribonucleoproteins that modulate multiple steps in RNA metabolic processes. Cytoplasmic aggregation of TDP-43 in affected neurons is a pathological hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Mislocalized and accumulated TDP-43 in the cytoplasm induces mitochondrial dysfunction and reactive oxidative species (ROS) production. Here, we show that TDP-43- and rotenone-induced neurotoxicity in the human neuronal cell line SH-SY5Y were attenuated by hydroxocobalamin (Hb, vitamin B<sub>12</sub> analog) treatment. Although Hb did not affect the cytoplasmic accumulation of TDP-43, Hb attenuated TDP-43-induced toxicity by reducing oxidative stress and mitochondrial dysfunction. Moreover, a shortened lifespan and motility defects in TDP-43-expressing <i>Drosophila</i> were significantly mitigated by dietary treatment with hydroxocobalamin. Taken together, these findings suggest that oral intake of hydroxocobalamin may be a potential therapeutic intervention for TDP-43-associated proteinopathies.https://www.mdpi.com/2076-3921/11/1/82TAR DNA-binding protein 43amyotrophic lateral sclerosis<i>Drosophila</i>mitochondrial dysfunctionoxidative stress |
| spellingShingle | Yu-Mi Jeon Younghwi Kwon Shinrye Lee Seyeon Kim Myungjin Jo Seongsoo Lee Sang Ryong Kim Kiyoung Kim Hyung-Jun Kim Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction Antioxidants TAR DNA-binding protein 43 amyotrophic lateral sclerosis <i>Drosophila</i> mitochondrial dysfunction oxidative stress |
| title | Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction |
| title_full | Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction |
| title_fullStr | Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction |
| title_full_unstemmed | Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction |
| title_short | Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction |
| title_sort | vitamin b12 reduces tdp 43 toxicity by alleviating oxidative stress and mitochondrial dysfunction |
| topic | TAR DNA-binding protein 43 amyotrophic lateral sclerosis <i>Drosophila</i> mitochondrial dysfunction oxidative stress |
| url | https://www.mdpi.com/2076-3921/11/1/82 |
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