論文 - 詳細
| RRC ID | 87977 |
|---|---|
| 著者 | Sun L, Liu J, Lu M, Zhou Y, Guo S, Qin Z, Wang Z, Sun X. |
| タイトル | Inactivation of SIAH-1 E3 ligase attenuates Aβ toxicity by suppressing ubiquitin-dependent DVE-1 degradation in Caenorhabditis elegans models of Alzheimer's disease. |
| ジャーナル | J Biol Chem |
| Abstract |
The mitochondrial unfolded protein response (UPRmt), an evolutionarily conserved proteostasis pathway, plays a critical role in the pathogenesis of Alzheimer's disease (AD), characterized by amyloid-β peptide (Aβ) aggregation. Although the transcription factor DVE-1 regulates UPRmt activation in Caenorhabditis elegans and has been implicated in Aβ pathology, its regulatory mechanisms under AD-like conditions remain unclear. Here, using the classical C. elegans muscle-specific AD model (CL2006 strain), we observed UPRmt induction in young adults despite paradoxical depletion of DVE-1 protein concurrent with elevated dve-1 transcript levels. Through integrated genetic and biochemical analyses, we identified SIAH-1, a conserved E3 ubiquitin ligase that partners with the E2 enzyme UBC-25 to interact with DVE-1 and mediate its K48-linked polyubiquitination, as targeting DVE-1 for proteasomal degradation. Disruption of SIAH-1 E3 ubiquitin ligase function or overexpression of DVE-1 significantly reduced Aβ toxicity in both the muscle-expressed Aβ (CL2006) and neuronal Aβ models (gnaIs2). These interventions concurrently suppressed Aβ aggregation in the heat shock-inducible Aβ aggregation model (xchIs15). Mechanistically, this protective effect was associated with restored mitochondrial homeostasis, as evidenced by MitoTracker Red staining and TOMM-20::mCherry fluorescence imaging in muscle-expressed Aβ animals. These assays demonstrated that Aβ accumulation compromises mitochondrial integrity, a phenotype markedly rescued in siah-1 deletion mutants and DVE-1-overexpressing strains. Collectively, these findings establish the SIAH-1/DVE-1 axis as a conserved proteostasis regulator and highlight ubiquitin-dependent mitochondrial quality control as a potential therapeutic target for AD and related proteopathies. |
| 巻・号 | 301(6) |
| ページ | 110226 |
| 公開日 | 2025-6-1 |
| DOI | 10.1016/j.jbc.2025.110226 |
| PII | S0021-9258(25)02076-9 |
| PMID | 40349774 |
| PMC | PMC12179603 |
| MeSH | Alzheimer Disease* / genetics Alzheimer Disease* / metabolism Alzheimer Disease* / pathology Amyloid beta-Peptides* / genetics Amyloid beta-Peptides* / metabolism Amyloid beta-Peptides* / toxicity Animals Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism Disease Models, Animal Humans Mitochondria / metabolism Proteolysis Seven in Absentia Proteins Ubiquitin* / metabolism Ubiquitin-Protein Ligases* / genetics Ubiquitin-Protein Ligases* / metabolism Ubiquitination Unfolded Protein Response |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | Bluesky |
| 各媒体での言及数の合計 | 1 |
| 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 | |
| 線虫 | tm1133 tm1968 |