Molecular Effects Of PS1Loss Of Function On Mitochondrial Apoptotic Pathway

Alzheimer’s disease (AD) is one of the most common central nervous system diseases, the currently prescribed drugs for AD treatment only provides improvement with limited efficacy without disease modifying. Genetic studies showed that mutations in presenilins1and2(PS1and PS2) are one of the causes of familial AD. Presenilins are the components of y-Secretase enzyme and are central to cleavage of APP. The mutations in PS lead to more production of Aβ42that result in extensive neuronal apoptosis, this has been suggested to be the "gain of toxic function of PS" attributed to AD pathology. PS1/PS2conditional knockout mice show similar neurodegenerative symptoms with AD patients including neuronal apoptosis and ventricle enlargement independent of Aβ deposition. We previously illustrated that there were mitochondrial dysfunction in cDKO mice, performance of alteration of membrane potential, fracture of crista and decreased expression of optic atrophy type1(OPA1) gene. These suggested us that loss function of PS may fundamentally relate to mitochondrial apoptosisthat may eventually lead to neuronal loss and progressive impairment in cognitive abilities. Presenilins-associated rhomboid-like (PARL) protein is a mitochondrial membrane proteins. PARL had been proved to involve in the abnormal cleavage of OPA1to regulate the remodeling of crista and cytochrome c (cyto C) release. To explore the molecular bases for interactions between the loss-of-function of PS and mitochondrial pathology that may implicates in pathogenesis of the early onset neuronal degeneration and apoptosis, we constructed a PS1knockdown SH-SY5Y stable cell line (PS-cell line). In this "PS loss of function" cell model we found declines of mitochondrial PARL and OPA1expressions at both mRNA and protein levels, which were further accompanied by cyto C release from the mitochondria, caspase3activation and cell death, suggesting a possible involvement of mitochondrial PS1-PARL-OPA1signaling in the apoptosis observed. Over expression of PARL in the PS1-cells significantly rescued the decrease of OPA1and reversed apoptosis signs. Over expression of PARL in the wide-type SH-SY5Y showed no change in the expression levels of PS1and OPA1and had no impact on apoptosis. Collectively, our study demonstrated that the loss function of PS1could significantly decrease the PARL expression and hereby lead to abnormal cleavage of OPA1, which might be eventually attributed to the activation of the mitochondrial PS1-PARL-OPA1apoptosis pathway. We further demonstrated that PARL played a key role in the signal transduction in this pathway and thus potentially served as a molecular target responsible for PS loss of function in early-onset AD-like neurodegeneration.