PS2 mutation increases neuronal cell vulnerability to neurotoxicants through activation of caspase‐3 by enhancing of ryanodine receptor‐mediated calcium release

Abstract

Increase of neuronal cell vulnerability by presenilin-2 (PS2) mutation by increase of caspase-3 activity through ryanodine receptor-mediated perturbation of calcium homeostasis was investigated. Stably transfected PC12 cells and cortical neurons from transgenic mice expressing mutant PS2 (N141I) showed a significantly enhanced sensitivity to L-glutamate, Aβ 25-35 , and Aβ 1-42 (ADDLs form) compared with cells expressing wild-type PS2. Consistent with this result, much greater intracellular calcium levels and caspase-3 activity were found in PC12 cells and cortical neurons expressing mutant PS2 after treatment with L-glutamate, Aβ 25-35 , and Aβ 1-42 . Double-labeling confocal micrographic and coimmunoprecipitation analyses showed that ryanodine receptor type 3 (RyR) and PS2 colocalize in the endoplasmic reticulum (ER) in PC12 cells and in the brain of transgenic mice. The expression of RyR was much higher in the neurons of cells expressing mutant PS2. Moreover, pretreatment with dantrolene, an agent that blocks calcium release from RyR, protected against the mutant PS2-enhanced neuronal cell death and caspase-3 activity. The present data indicate that activation of caspase-3 by RyR-mediated increase of intracellular calcium levels may be an important neurotoxic mechanism in the neuronal cells expressing mutant PS2.

Ryanodine receptor-mediated interference of neuronal cell differentiation by presenilin 2 mutation

“…Consistent with normal cell differentiation, and similar to what was observed in the brains of nontrangenic mice in a previous study (Lee et al, 2005), RyR was detectably expressed in the neuronal cells of nontransgenic mice (data not shown). RyR expression was detected in neuronal cells, and it was found to be increased by treatment with caffeine (30 mM), an RyR agonist during cell differentiation; visualized by immunocytochemistry with fluorescence dye ( Fig.…”

“…In addition, it was reported that PS2 interacts with sorcin, a modulator of RyR (Pack-Chung et al, 2000). Our previous data also show that PS2 colocalizes with type 3 RyR in neurons (Lee et al, 2005). Therefore, our data suggest that alterations of RyR may be involved in the PS2 mutation-induced disruption of neuronal cell differentiation.…”

“…We previously found that transgenic mice expressing mutant PS2 show significant memory dysfunction and neuronal cell death (Hwang et al, 2002) in addition to a significant increase in intracellular calcium levels through RyR activation (Lee et al, 2005). In the present study, we investigated whether RyR-mediated calcium overrelease can cause deficits in neurogenesis in neuronal cells expressing mutant PS2.…”

Inhibitory effect of snake venom toxin from Vipera lebetina turanica on hormone-refractory human prostate cancer cell growth: induction of apoptosis through inactivation of nuclear factor κB

“…Cell cultures were then maintained at 37jC in a humidified atmosphere with 5% CO 2 . RAW 264.7 macrophage cells (16) and primary neuronal cells (17) were prepared and cultured as previously described.…”

Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer’s disease pathogenesis

“…In addition, RyanR protein levels and channel function are increased in mouse models of containing PS mutations PS1-M146V and PS2-N141I [41][42][43]. Clinical mutations of PS2 also enhanced Ca 2+ release from IP 3 R-gated ER stores [44].…”