br Presenilins and apoptosis Apoptosis also known as program
Presenilins and apoptosis Apoptosis, also known as programmed cell death, has a critically important role in tissue homeostasis, development, normal ageing and the pathogenesis of several diseases, including cancer and neurological disorders. The presenilins were first linked to apoptosis when cells expressing PS1 FAD mutants were shown to have increased susceptibility to apoptotic stimuli , , , . Similarly, expression of PS1 and PS2 in HeLa cells has been shown to cause ARRY-142886 arrest and apoptosis, a process that is increased with the expression of PS1 and PS2 FAD mutants , , . However, primary cortical neurons from PS1 FAD P264L mutant knock-in mice did not show increased neuron degeneration, suggesting that not all FAD mutations promote apoptosis , . Cells undergo apoptosis through two converging pathways : the extrinsic pathway, mediated by cell surface death receptors, and the intrinsic pathway, which depends upon the release of pro-apoptotic cytochrome-c from the mitochondria (Fig. 5). In the extrinsic pathway, following ligand binding and activation of a death receptor, such as FAS or TNFR1, recruitment of the adaptor Fas-associated protein with death domain (FADD) and pro-caspase-8 leads to the formation of the death-inducing signalling complex (DISC), culminating in the activation of caspase-8, which in turn leads to the activation of effector caspase-3 and caspase-7, resulting in DNA fragmentation and programmed cell death. In the intrinsic pathway, extracellular and intracellular stresses lead to the activation and translocation of the pro-apoptotic Bcl-2 family member Bax to the mitochondria. Bax thereby initiates the release of apoptogenic factors, such as cytochrome-c, resulting in the formation of the cytoplasmic apoptosome, consisting of Apaf-1, pro-caspase-9 and cytochrome-c. Once activated, caspase-9 leads to the activation of caspase-3 and caspase-7. Both pathways can converge through caspase-8-mediated activation of Bid, which subsequently promotes translocation of Bax to the mitochondria. Consistent with a role in cell survival the presenilin proteins are cleaved by caspase-3 during apoptosis to presumably form inactive alternative NTF and CTF fragments for each protein , . Furthermore, the presenilins have been reported to interact with the anti-apoptotic proteins Bcl-2 and Bcl-XL and with other apoptosis related proteins such as PS1-associated protein (PSAP), FKBP38, Omi/HtrAS and PARL, though the physiological relevance of these reported interactions remains to be determined . Other studies have demonstrated that increased resistance to apoptosis parallels loss of PS1 expression, while murine B-cells deficient in PS2 show an increased susceptibility to induced apoptosis . Consistent with this, overexpression of PS1 is able to reduce p53-mediated apoptosis in the LTR6 mouse leukaemia cell line , while PS2 expression enhances apoptosis via p53 where it increases Bax expression and reduces Bcl-2 expression . This increase in apoptosis is mediated by the PS2 CTF, which increases p53 mediated gene transcription in a γ-secretase independent manner . The presenilin proteins can also affect p53 activity in a γ-secretase dependent manner in that the production of the APP ICD leads to increased p53 expression . Recently efforts were made to define the molecular pathways that mediate the apoptotic effects of PS1, whereby it has been shown that PS1 regulates apoptosis in both γ-secretase-dependent and -independent ways via cellular-FLICE-like inhibitory protein (c-FLIP) and the PS1 associated protein (PSAP), respectively . PSAP has been shown to regulate apoptosis via the intrinsic apoptosis pathway, by controlling the release of cytochrome-c from the mitochondria (Fig. 5) . Silencing of Bax repressed this γ-secretase-independent apoptotic pathway , suggesting that the interaction between PS1 and PSAP plays a γ-secretase independent role in regulating the mitochondrial apoptotic pathway. The FKBP38 protein modulates this presenilin-mediated apoptosis, as FKBP38 knockout cells alter Bcl-2 cell localization protecting them from presenilin-mediated apoptosis . Therefore, both presenilin proteins can be seen to play distinct roles in regulating apoptosis, however presenilins may indirectly regulate apoptosis through their association with calcium homeostasis, protein degradation and other pathways, of which the underlying molecular mechanisms are emerging.