The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models
Spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is obser...
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Frontiers Media S.A.
2017-06-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00196/full |
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| author | Jung-Yu Hsu Jung-Yu Hsu Yu-Ling Jhang Pei-Hsun Cheng Yu-Fan Chang Su-Han Mao Han-In Yang Chia-Wei Lin Chuan-Mu Chen Shang-Hsun Yang Shang-Hsun Yang |
| author_facet | Jung-Yu Hsu Jung-Yu Hsu Yu-Ling Jhang Pei-Hsun Cheng Yu-Fan Chang Su-Han Mao Han-In Yang Chia-Wei Lin Chuan-Mu Chen Shang-Hsun Yang Shang-Hsun Yang |
| author_sort | Jung-Yu Hsu |
| collection | DOAJ |
| description | Spinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is observed to cause neuronal death in SCA3 patients. Based on previous studies, proteolytic cleavage of mutant ATXN3 is found to produce truncated C-terminal fragments in SCA3 models. However, whether these truncated mutant fragments disturb mitochondrial functions and result in pathological death is still unclear. Here, we used neuroblastoma cell and transgenic mouse models to examine the effects of truncated mutant ATXN3 on mitochondria functions. In different models, we observed truncated mutant ATXN3 accelerated the formation of aggregates, which translocated into the nucleus to form intranuclear aggregates. In addition, truncated mutant ATXN3 caused more mitochondrial fission, and decreased the expression of mitochondrial fusion markers, including Mfn-1 and Mfn-2. Furthermore, truncated mutant ATXN3 decreased the mitochondrial membrane potential, increased reactive oxygen species and finally increased cell death rate. In transgenic mouse models, truncated mutant ATXN3 also led to more mitochondrial dysfunction, neurodegeneration and cell death in the cerebellums. This study supports the toxic fragment hypothesis in SCA3, and also provides evidence that truncated mutant ATXN3 is severer than full-length mutant one in vitro and in vivo. |
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| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-13T02:18:16Z |
| publishDate | 2017-06-01 |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-8d43b7c30a75490ca2ebc3bbbaba994d2022-12-22T03:07:05ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-06-011010.3389/fnmol.2017.00196268929The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 ModelsJung-Yu Hsu0Jung-Yu Hsu1Yu-Ling Jhang2Pei-Hsun Cheng3Yu-Fan Chang4Su-Han Mao5Han-In Yang6Chia-Wei Lin7Chuan-Mu Chen8Shang-Hsun Yang9Shang-Hsun Yang10Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan, TaiwanDepartment of Cell Biology and Anatomy, College of Medicine, National Cheng Kung UniversityTainan, TaiwanDepartment of Physiology, College of Medicine, National Cheng Kung UniversityTainan, TaiwanDepartment of Physiology, College of Medicine, National Cheng Kung UniversityTainan, TaiwanDepartment of Physiology, College of Medicine, National Cheng Kung UniversityTainan, TaiwanDepartment of Physiology, College of Medicine, National Cheng Kung UniversityTainan, TaiwanDepartment of Physiology, College of Medicine, National Cheng Kung UniversityTainan, TaiwanDepartment of Physiology, College of Medicine, National Cheng Kung UniversityTainan, TaiwanDepartment of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing UniversityTaichung, TaiwanInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung UniversityTainan, TaiwanDepartment of Physiology, College of Medicine, National Cheng Kung UniversityTainan, TaiwanSpinocerebellar ataxia type 3 (SCA3), known as Machado-Joseph disease, is an autosomal dominant disease caused by an abnormal expansion of polyglutamine in ATXN3 gene, leading to neurodegeneration in SCA3 patients. Similar to other neurodegenerative diseases, the dysfunction of mitochondria is observed to cause neuronal death in SCA3 patients. Based on previous studies, proteolytic cleavage of mutant ATXN3 is found to produce truncated C-terminal fragments in SCA3 models. However, whether these truncated mutant fragments disturb mitochondrial functions and result in pathological death is still unclear. Here, we used neuroblastoma cell and transgenic mouse models to examine the effects of truncated mutant ATXN3 on mitochondria functions. In different models, we observed truncated mutant ATXN3 accelerated the formation of aggregates, which translocated into the nucleus to form intranuclear aggregates. In addition, truncated mutant ATXN3 caused more mitochondrial fission, and decreased the expression of mitochondrial fusion markers, including Mfn-1 and Mfn-2. Furthermore, truncated mutant ATXN3 decreased the mitochondrial membrane potential, increased reactive oxygen species and finally increased cell death rate. In transgenic mouse models, truncated mutant ATXN3 also led to more mitochondrial dysfunction, neurodegeneration and cell death in the cerebellums. This study supports the toxic fragment hypothesis in SCA3, and also provides evidence that truncated mutant ATXN3 is severer than full-length mutant one in vitro and in vivo.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00196/fulltruncated aTXN3spinocerebellar ataxia type 3mitochondria dynamicstransgenic miceneurodegenerationfusion and fission |
| spellingShingle | Jung-Yu Hsu Jung-Yu Hsu Yu-Ling Jhang Pei-Hsun Cheng Yu-Fan Chang Su-Han Mao Han-In Yang Chia-Wei Lin Chuan-Mu Chen Shang-Hsun Yang Shang-Hsun Yang The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models Frontiers in Molecular Neuroscience truncated aTXN3 spinocerebellar ataxia type 3 mitochondria dynamics transgenic mice neurodegeneration fusion and fission |
| title | The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models |
| title_full | The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models |
| title_fullStr | The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models |
| title_full_unstemmed | The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models |
| title_short | The Truncated C-terminal Fragment of Mutant ATXN3 Disrupts Mitochondria Dynamics in Spinocerebellar Ataxia Type 3 Models |
| title_sort | truncated c terminal fragment of mutant atxn3 disrupts mitochondria dynamics in spinocerebellar ataxia type 3 models |
| topic | truncated aTXN3 spinocerebellar ataxia type 3 mitochondria dynamics transgenic mice neurodegeneration fusion and fission |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2017.00196/full |
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