論文 - 詳細
| RRC ID | 31968 |
|---|---|
| 著者 | Menzies FM, Garcia-Arencibia M, Imarisio S, O'Sullivan NC, Ricketts T, Kent BA, Rao MV, Lam W, Green-Thompson ZW, Nixon RA, Saksida LM, Bussey TJ, O'Kane CJ, Rubinsztein DC. |
| タイトル | Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity. |
| ジャーナル | Cell Death Differ |
| Abstract |
Over recent years, accumulated evidence suggests that autophagy induction is protective in animal models of a number of neurodegenerative diseases. Intense research in the field has elucidated different pathways through which autophagy can be upregulated and it is important to establish how modulation of these pathways impacts upon disease progression in vivo and therefore which, if any, may have further therapeutic relevance. In addition, it is important to understand how alterations in these target pathways may affect normal physiology when constitutively modulated over a long time period, as would be required for treatment of neurodegenerative diseases. Here we evaluate the potential protective effect of downregulation of calpains. We demonstrate, in Drosophila, that calpain knockdown protects against the aggregation and toxicity of proteins, like mutant huntingtin, in an autophagy-dependent fashion. Furthermore, we demonstrate that, overexpression of the calpain inhibitor, calpastatin, increases autophagosome levels and is protective in a mouse model of Huntington's disease, improving motor signs and delaying the onset of tremors. Importantly, long-term inhibition of calpains did not result in any overt deleterious phenotypes in mice. Thus, calpain inhibition, or activation of autophagy pathways downstream of calpains, may be suitable therapeutic targets for diseases like Huntington's disease. |
| 巻・号 | 22(3) |
| ページ | 433-44 |
| 公開日 | 2015-3-1 |
| DOI | 10.1038/cdd.2014.151 |
| PII | cdd2014151 |
| PMID | 25257175 |
| PMC | PMC4326573 |
| MeSH | Animals Autophagy / drug effects* Calcium-Binding Proteins / biosynthesis Calpain / antagonists & inhibitors* Calpain / genetics Calpain / metabolism Disease Models, Animal Drosophila Drosophila Proteins / antagonists & inhibitors Drosophila Proteins / genetics Drosophila Proteins / metabolism Female Gene Knockdown Techniques Huntington Disease / enzymology Huntington Disease / metabolism* Huntington Disease / pathology* Huntington Disease / therapy Inbreeding Male Mice Mice, Inbred C57BL Peptides / metabolism* Signal Transduction |
| IF | 10.717 |
| 引用数 | 52 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 7 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ショウジョウバエ | 7563R-1 18152R-2 |