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

Abstract

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 Caenorhabditis elegans , 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 sel-12 or ryr-1 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 sel-12 mutants. Notably, sel-12 loss does not alter ryr-1 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.