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  • Therefore as it stands presenilin has a secretase independen

    2022-05-26

    Therefore as it stands, presenilin has a γ-secretase-independent role in regulating protein trafficking, proteolysis and degradation, however given that inhibition of γ-secretase activity can have a negative effect on protein trafficking [69], [98], we cannot exclude the possibility that some of the trafficking defects seen in CT-99021 with compromised PS1 expression of activity may be attributed to loss or reduced cleavage of Vsp10p sorting receptors or other substrates.
    Presenilins and calcium homeostasis Additional to the proposed secondary effects of PS1 on lysosomal calcium storage and homeostasis outlined above, another proposed ancestral role for presenilins relates to the formation of ER calcium leak channels and the regulation of intracellular calcium homeostasis (Fig. 4) [99], [100]. Disrupted calcium signalling has been reported to precede the classic AD pathologies, neurofibrillary tangles and Aβ plaques, and is proposed to contribute to neuronal cell death during AD [101]. Similarly, in numerous mouse models of AD increased basal levels of Ca have been observed and presenilin FAD mutations have been observed to cause changes in Ca levels [93], [100], [102], [103]. There are several lines of evidence supporting a role for presenilins in the regulation of calcium homeostasis of intracellular stores, which appear to be independent of γ-secretase protease activities (Fig. 4). First, the presenilins interact with several proteins functionally involved in calcium signalling, including sorcin, calmodulin, calsenilin, calmyrin and calpain [104], [105], [106]. It was next proposed that presenilin holoproteins act as passive Ca channels in the ER and those PS FAD mutations alter channel conductance [93]. In an elegant mutagenesis study it was subsequently demonstrated that the hydrophilic catalytic cavity of PS1 facilitates the formation of a calcium leak conductance pore [107]. In parallel, the presenilins have been shown to regulate Ca levels through interactions with and activation of Ca channels such the sarco/ER Ca-ATPase (SERCA) pump [108], the inositol triphosphate receptor (InsP3R) [109], and the Ryanodine receptor (RyR) [110], [111]. More recently the presenilins have also been reported to modulate phosphatidylinositol-4,5-bisphosphate (PIP2)-mediated regulation of the transition receptor potential of melastatin related 7 (TRPM7) [112]. Finally, the presenilins have also been proposed to increase the number of contact sites between the ER and mitochondria, thereby facilitating movement of Ca from the ER to the mitochondria [113]. Further indicating a γ-secretase-independent role for the presenilins in regulating calcium homeostasis, presenilin-deficient MEFs show a decrease in ER Ca concentration, which may be as a result of the presenilins regulating InsP3R levels [114] or SERCA pump levels leading to increased ER [Ca] [108], which in both cases normal Ca levels can be rescued by overexpression of presenilin holoproteins. Mouse models expressing PS1 FAD mutants show constitutive activation of cAMP response element binding (CREB) gene expression, which is eliminated by inhibition of InsP3R [115]. Furthermore, PS1 FAD M146V mutant knock-in hippocampal cells showed reduced synaptic plasticity and defects in long-term potentiation (LTP), which can be rescued by inhibition of the RyR [99]. Conditional knockout of presenilins or expression of the PS1 FAD M146V mutant in mouse hippocampal cells has also been shown to increase ER Ca levels and enhance susceptibility to induced Ca release [100]. These cells also showed an increase in ER RyR levels, which the authors suggest, maybe a result of the decreased presenilin leak channel function, leading to the increased ER Ca levels and thus a need for an increase in ER Ca channel expression. Additionally, downregulation of PS1 via inhibition of JNK or P53 has been shown to decrease ER Ca leakage without altering InsP3R expression [116]. Consistent with these mammalian studies and supportive of an evolutionary conserved function, X-ray crystallography studies of a presenilin archaeal homologue PSH have shown the presence of a hole that passes through the protein formed from TMD2, TMD3, TMD5 and TMD7, separate to the catalytic core of the enzyme, that is large enough to allow small ions to pass through [117]. Despite all of these studies, some controversies have been raised by reports of the direct measurement of Ca ER release from primary neurons, fibroblasts, B-cells and hippocampal neurons [118], [119], which showed no difference in ER Ca dynamics between cells expressing PS1 WT and PS1 FAD mutants and that any change in ER [Ca] in presenilin-deficient cells was not due to increased ER filling CT-99021 [118]. Therefore, while the presenilins have been shown to be important in regulating intracellular Ca via several proposed mechanisms, as it stands the Ca leak channel function theory of the presenilins remains controversial.