Calreticulin (crt-1) silencing reduces Aß1–42-induced toxicity and restores muscle function in C. elegans.
Accumulation of aggregated β-amyloid peptide is a key histopathological feature of Alzheimer's Disease (AD). Experimental models of AD based on β-amyloid peptide display calcium (Ca2+) signaling alterations, and targeting key components of the cellular Ca2+ signaling system has been postulated...
| Authors: | , , , , , , , , |
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| Format: | article |
| Status: | Published version |
| Publication Date: | 2025 |
| Country: | España |
| Institution: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repository: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/399697 |
| Online Access: | http://hdl.handle.net/10261/399697 |
| Access Level: | Open access |
| Keyword: | C. elegans Calreticulin Crt-1 Alzheimer's disease beta-amyloid Mitochondria Ca2+ signaling |
| Summary: | Accumulation of aggregated β-amyloid peptide is a key histopathological feature of Alzheimer's Disease (AD). Experimental models of AD based on β-amyloid peptide display calcium (Ca2+) signaling alterations, and targeting key components of the cellular Ca2+ signaling system has been postulated to modulate AD onset and progression. Here we have taken advantage of a C. elegans strain that over-expresses the most toxic human ß-amyloid peptide (Aß1–42) in body-wall muscle cells, to study the impact of calreticulin (crt-1) silencing on body-wall muscle performance. Crt-1 knockdown reduced the percentage of paralyzed worms in a dose-dependent manner and improved locomotion parameters in free-mobility assays in Aß1–42-overexpressing worms. At the cellular level, crt-1 silencing prevented Aß1–42-induced exacerbated mitochondrial respiration and mitochondrial ROS production without impacting mitochondrial sarcomere organization. Crt-1 knockdown reduced the number and size of Aß1–42 aggregates in body-wall muscle cells and prevented the formation of Aß1–42 oligomers. We propose that crt-1 depletion reduces the number of Aß1–42 aggregates, precluding Aß1–42-induced mitochondrial toxicity and improving muscle function. We identify C. elegans crt-1 as a gene involved in the toxicity associated with the expression of human Aß1–42, and thus a potential new target for treatment. |
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