Molecular Investigation Into The Effects Of Presenilin 1 Deficiency On The Interaction Between Mitochondria And ER Towards Neuronal Survival Or Death

Presenilin 1?PS1?and Presenilin 2?PS2?are the essential part of?-secretase and they play crucial role in synaptogenesis,neuronal differentiation,Ca²⁺transmission and also neurotransmitter release.Though it is verified in PS1/2 conditional double knock out?cDKO?mice that presenilins deficiency would result in enlarged ventricle,posterior cortical atrophy and neuronal apoptosis in brain which mimic the pathological phenotypes observed in the early-onset of Alzheimer's disease,we know little about the molecular mechanism underlying these pathological changes.Our previous studies both in SHSY5Y model and the PS1/2 cDKO mice showed that PS1 deficiency could induce neuronal apoptosis via a PARL?presenilins-associated rhomboid-like protein?related mitochondrial apoptosis signaling pathway,which could be rescued by proper modulation of ER stress.Mitochondria-associated ER membrane?MAM?has important role in cellular metabolic activities,including Ca²⁺homeostasis,cholesterol and phospholipid metabolism,and also the function and dynamics of mitochondria,due to the tight association both physically and biochemically between mitochondria and ER.This study aimed to investigate the functional effects of PS1 deficiency on the structure and function of MAM and the modulation of the interaction of MAM with PARL-related mitochondrial signaling pathway.Using the transmission electron microscopy and the double-labelled fluorescence approaches,we first observed a damaged change of MAM in PS1/2 cDKO mice.This result was confirmed and further supported by the findings of disturbed mitochondrial calcium homeostasis in the PS1 knockdown SHSY5Y cell model,suggesting a deleterious functional interaction or communication between ER and mitochondria in response to PS1 deficiency.Such PS1 deficiency-mediated structural and functional impairment of MAM,however,could be rescued either by proper regulation of ER stress or overexpression of PARL in the cells.The results,together with our previous findings,might thus suggest that,following PS1 deficiency,mitochondrial PARL may be in the central position in determining the fate,i.e.,survival or death,of neuronal cells.