| Autor: |
Shun Mitsui, Asako Otomo, Masahisa Nozaki, Suzuka Ono, Kai Sato, Ryohei Shirakawa, Hiroaki Adachi, Masashi Aoki, Gen Sobue, Hui-Fang Shang, Shinji Hadano |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
Molecular Brain, Vol 11, Iss 1, Pp 1-16 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
1756-6606 |
| DOI: |
10.1186/s13041-018-0373-8 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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