SERCA Silencing Alleviates Aß(1-42)-Induced Toxicity in a C. elegans Model

The Sarco Endoplasmic Reticulum Ca²⁺-ATPase (SERCA) pumps cytosolic Ca²⁺ into the endoplasmic reticulum lumen (ER) to maintain cytosolic and ER Ca²⁺ levels under physiological conditions. Previous reports suggest that cellular Ca²⁺ homeostasis is compromised in Alzheimer's Disease (AD) and that SERCA activity can modulate the phenotype of AD mouse models. Here, we used a <i>C. elegans</i> strain that overexpresses the most toxic human ß-amyloid peptide (Aß_(1-42)) in body-wall muscle cells to study the effects of SERCA (<i>sca-1</i>) silencing on Aß_(1-42)-induced body-wall muscle dysfunction. <i>sca-1</i> knockdown reduced the percentage of paralyzed worms, improved locomotion in free-mobility assays, and restored pharynx pumping in Aß_(1-42)-overexpressing worms. At the cellular level, <i>sca-1</i> silencing partially prevented Aß_(1-42)-induced exacerbated mitochondrial respiration and mitochondrial ROS production and restored mitochondrial organization around sarcomeres. <i>sca-1</i> knockdown reduced the number and size of Aß_(1-42) aggregates in body-wall muscle cells and prevented the formation of Aß_(1-42) oligomers. Aß_(1-42) expression induced a slower kinetics of spontaneous cytosolic Ca²⁺ transients in muscle cells and <i>sca-1</i> partially restored these changes. We propose that partial <i>sca-1</i> loss of function prevents the toxicity associated with beta-amyloid accumulation by reducing the formation of Aß_(1-42) oligomers and improving mitochondrial function, in a mechanism that requires remodeling of cytosolic Ca²⁺ dynamics and partial ER Ca²⁺ depletion.