Presenilin Loss Impairs Synaptic Transmission and Causes Axonal Degeneration through Ryanodine Receptor Dysfunction, Independent of γ-Secretase Activity

Presenilin mutations are the most common cause of familial Alzheimer's disease (FAD), but the mechanisms by which they disrupt neuronal function remain unresolved, particularly in relation to γ-secretase activity. Using <i>Caenorhabditis elegans</i>, we show that the presenilin ortholog SEL-12 supports synaptic transmission and axonal integrity through a pathway involving the ryanodine receptor RYR-1. Loss-of-function mutations in either <i>sel-12</i> or <i>ryr-1</i> reduce neurotransmitter release and cause neuronal structural defects, with no additional impairment in double mutants, suggesting a shared pathway. Transgenic expression of a γ-secretase-inactive SEL-12 variant or human presenilin 1 restores normal synaptic transmission in <i>sel-12</i> mutants. Notably, <i>sel-12</i> loss does not alter <i>ryr-1</i> transcript or protein levels. These findings define a novel γ-secretase-independent role of presenilin in maintaining neuronal function via ryanodine receptor signaling, providing new mechanistic insight into presenilin-linked neurodegeneration and pointing to potential therapeutic strategies for FAD.