Inactivation of SIAH-1 E3 ligase attenuates Aβ toxicity by suppressing ubiquitin-dependent DVE-1 degradation in Caenorhabditis elegans models of Alzheimer's disease.

The mitochondrial unfolded protein response (UPR), 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 UPR 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 UPR 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.