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 C. 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 for 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.Significance Statement Mutations in presenilins are the major cause of familial Alzheimer's disease and are commonly associated with impaired synaptic transmission and neurodegeneration. However, the molecular mechanisms underlying these effects remain poorly understood. This study shows that loss of presenilin in C. elegans impairs neurotransmitter release and causes axonal degeneration through dysfunction of ryanodine receptors (RyRs), independent of presenilin's γ-secretase activity. Notably, RyR expression remains unchanged, suggesting that presenilins likely regulate RyR function. These findings uncover a γ-secretase-independent pathway linking presenilin dysfunction to synaptic and neuronal deficits. The findings of this study offer new insight into the pathogenesis of Alzheimer's disease.