Reference - Detail
| RRC ID | 31968 |
|---|---|
| Author | 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. |
| Title | Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity. |
| Journal | 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. |
| Volume | 22(3) |
| Pages | 433-44 |
| Published | 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 |
| Times Cited | 52 |
| WOS Category | BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 7 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Drosophila | 7563R-1 18152R-2 |