Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse model
Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Recent studies have shown that mutations in SQSTM1 are linked to ALS. SQSTM1 encodes SQSTM1/p62 that regulates not only autophagy via the associ...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-05-01
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| Series: | Molecular Brain |
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| Online Access: | http://link.springer.com/article/10.1186/s13041-018-0373-8 |
| _version_ | 1818621537994932224 |
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| author | Shun Mitsui Asako Otomo Masahisa Nozaki Suzuka Ono Kai Sato Ryohei Shirakawa Hiroaki Adachi Masashi Aoki Gen Sobue Hui-Fang Shang Shinji Hadano |
| author_facet | Shun Mitsui Asako Otomo Masahisa Nozaki Suzuka Ono Kai Sato Ryohei Shirakawa Hiroaki Adachi Masashi Aoki Gen Sobue Hui-Fang Shang Shinji Hadano |
| author_sort | Shun Mitsui |
| collection | DOAJ |
| description | Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Recent studies have shown that mutations in SQSTM1 are linked to ALS. SQSTM1 encodes SQSTM1/p62 that regulates not only autophagy via the association with MAP1LC3/LC3 and ubiquitinated proteins but also the KEAP1-NFE2L2/Nrf2 anti-oxidative stress pathway by interacting with KEAP1. Previously, we have demonstrated that loss of SQSTM1 exacerbates disease phenotypes in a SOD1H46R-expressing ALS mouse model. To clarify the effects of SQSTM1 overexpression in this model, we generated SQSTM1 and SOD1 H46R double-transgenic (SQSTM1;SOD1 H46R ) mice. SQSTM1;SOD1 H46R mice exhibited earlier disease onset and shorter lifespan than did SOD1 H46R mice. Conversely, disease progression after the onset rather slightly but significantly slowed in SQSTM1;SOD1 H46R mice. However, there were observable differences neither in the number of Nissl positive neurons nor in the distribution of ubiquitin-positive and/or SQSTM1-positive aggregates between SOD1 H46R and SQSTM1;SOD1 H46R mice. It was noted that these protein aggregates were mainly observed in neuropil, and partly localized to astrocytes and/or microglia, but not to MAP2-positive neuronal cell bodies and dendrites at the end-stage of disease. Nonetheless, the biochemically-detectable insoluble SQSTM1 and poly-ubiquitinated proteins were significantly and progressively increased in the spinal cord of SQSTM1;SOD1 H46R mice compared to SOD1 H46R mice. These results suggest that overexpression of SQSTM1 in SOD1 H46R mice accelerates disease onset by compromising the protein degradation pathways. |
| first_indexed | 2024-12-16T18:10:52Z |
| format | Article |
| id | doaj.art-8580ca713204450288e370952c8766f7 |
| institution | Directory Open Access Journal |
| issn | 1756-6606 |
| language | English |
| last_indexed | 2024-12-16T18:10:52Z |
| publishDate | 2018-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Brain |
| spelling | doaj.art-8580ca713204450288e370952c8766f72022-12-21T22:21:47ZengBMCMolecular Brain1756-66062018-05-0111111610.1186/s13041-018-0373-8Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse modelShun Mitsui0Asako Otomo1Masahisa Nozaki2Suzuka Ono3Kai Sato4Ryohei Shirakawa5Hiroaki Adachi6Masashi Aoki7Gen Sobue8Hui-Fang Shang9Shinji Hadano10Department of Molecular Life Sciences, Tokai University School of MedicineDepartment of Molecular Life Sciences, Tokai University School of MedicineDepartment of Molecular Life Sciences, Tokai University School of MedicineDepartment of Molecular Life Sciences, Tokai University School of MedicineDepartment of Molecular Life Sciences, Tokai University School of MedicineDepartment of Molecular Life Sciences, Tokai University School of MedicineDepartment of Neurology, University of Occupational and Environmental Health School of MedicineDepartment of Neurology, Tohoku University Graduate School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineDepartment of Neurology, West China Hospital, Sichuan UniversityDepartment of Molecular Life Sciences, Tokai University School of MedicineAbstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Recent studies have shown that mutations in SQSTM1 are linked to ALS. SQSTM1 encodes SQSTM1/p62 that regulates not only autophagy via the association with MAP1LC3/LC3 and ubiquitinated proteins but also the KEAP1-NFE2L2/Nrf2 anti-oxidative stress pathway by interacting with KEAP1. Previously, we have demonstrated that loss of SQSTM1 exacerbates disease phenotypes in a SOD1H46R-expressing ALS mouse model. To clarify the effects of SQSTM1 overexpression in this model, we generated SQSTM1 and SOD1 H46R double-transgenic (SQSTM1;SOD1 H46R ) mice. SQSTM1;SOD1 H46R mice exhibited earlier disease onset and shorter lifespan than did SOD1 H46R mice. Conversely, disease progression after the onset rather slightly but significantly slowed in SQSTM1;SOD1 H46R mice. However, there were observable differences neither in the number of Nissl positive neurons nor in the distribution of ubiquitin-positive and/or SQSTM1-positive aggregates between SOD1 H46R and SQSTM1;SOD1 H46R mice. It was noted that these protein aggregates were mainly observed in neuropil, and partly localized to astrocytes and/or microglia, but not to MAP2-positive neuronal cell bodies and dendrites at the end-stage of disease. Nonetheless, the biochemically-detectable insoluble SQSTM1 and poly-ubiquitinated proteins were significantly and progressively increased in the spinal cord of SQSTM1;SOD1 H46R mice compared to SOD1 H46R mice. These results suggest that overexpression of SQSTM1 in SOD1 H46R mice accelerates disease onset by compromising the protein degradation pathways.http://link.springer.com/article/10.1186/s13041-018-0373-8Amyotrophic lateral sclerosisSOD1SQSTM1/p62Ubiquitin-positive aggregates |
| spellingShingle | Shun Mitsui Asako Otomo Masahisa Nozaki Suzuka Ono Kai Sato Ryohei Shirakawa Hiroaki Adachi Masashi Aoki Gen Sobue Hui-Fang Shang Shinji Hadano Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse model Molecular Brain Amyotrophic lateral sclerosis SOD1 SQSTM1/p62 Ubiquitin-positive aggregates |
| title | Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse model |
| title_full | Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse model |
| title_fullStr | Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse model |
| title_full_unstemmed | Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse model |
| title_short | Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse model |
| title_sort | systemic overexpression of sqstm1 p62 accelerates disease onset in a sod1h46r expressing als mouse model |
| topic | Amyotrophic lateral sclerosis SOD1 SQSTM1/p62 Ubiquitin-positive aggregates |
| url | http://link.springer.com/article/10.1186/s13041-018-0373-8 |
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