Versatility of presenilin 1.

Mutations in PSEN1 and PSEN2 genes, encoding presenilin 1 (PS1) and presenilin 2 (PS2), respectively, cause autosomal-dominant Alzheimer’s disease (ADAD) (1, 2). The precise mechanism by which PS1 mutations lead to AD is under active investigation. Multiple theories have been suggested to explain the role of PS1 and PS2 mutations on AD pathogenesis, including the effects on γ-secretase activity and specificity (3–6), protein trafficking (7), β-catenin pathway (8), calcium homoeostasis (9), and the lysosomal/autophagy pathway (10). In PNAS, Bustos et al. (11, 12) show an unprecedented role for PS1 in autophagic degradation of βCTF and, consequently, reduction of Aβ. Moreover, they offer an underlying mechanism in which PS1 is phosphorylated at Ser367 by CK1γ2 that recruits AnxA2 to initiate autophagic machinery. Importantly, this discovery leads to a novel avenue for treatment of AD. β-Secretase and γ-secretase sequentially cleave the amyloid precursor protein (APP) to generate the N terminus and C terminus of Aβ, respectively. Investigation of PS has paralleled identification of γ-secretase. (i ) ADAD mutations in PSEN1 and PSEN2 cause an increase in the ratio of Aβ42/Aβ40 in transfected cells and in transgenic mice (3–5). (ii) Isolated cultured neurons derived from PS1-deficient mice showed significantly reduced Aβ production and accumulate APP fragments that fail to be processed by γ-secretase (13). (iii) Mutagenesis of two conserved aspartate residues in the transmembrane regions of PS1 significantly reduces γ-secretase activity (14). (iv) AntiPS1 antibodies capture γ-secretase activity. Furthermore, γ-secretase activity is associated with PS-containing macromolecular complexes (15). (v) Active-site directed γ-secretase inhibitors directly bind to PS1 or PS2 (16, 17). (vi) γ-Secretase activity can be reconstituted using a recombinant PS1 variant alone, offering the final proof that PS is the catalytic subunit of the γ-secretase complex (18). In cells, γ-secretase relies on the assembly of an active enzyme complex that is composed of four proteins: Nicastrin, PS, Pen-2, and Aph-1 (19). PS1 and PS2 undergo endoproteolysis and the Nand C-terminal cleavage products (NTF and CTF) remain associated within the γ-secretase complex (19, 20). The recent reports of cryoelectron microscopy structures of intact human γ-secretase have offered novel insights into the function and assembly of this enzyme (21). It is known that only a small portion of the γ-secretase complex is catalytically active (22) and the inactive complex can be activated in response to environmental changes (23). Phosphorylation of PS1 has been widely investigated, and it seems that there is little effect on γ-secretase activity (24). Recently, Maesako et al. (25) reported that phosphorylation of PS1 at Thr74, Ser313, Ser365, Ser366, or Ser367 is critical to induce a pathogenic “closed” conformation, which may lead to an increase on the ratio of Aβ42/Aβ40. Bustos et al. (11, 12) find that phosphorylation of Ser367 serves as a switch to promote autophagy-mediated degradation of βCTF (Fig. 1), which ultimately leads to a reduction in Aβ production. Otherwise, the nonphosphorylated complex cleaves βCTF to generate Aβ. Substitution of Ser367 by Ala does not affect γ-secretase activity but leads to an accumulation of soluble and insoluble Aβ (Aβ40 and Aβ42) and plaques in J20-S367Amouse brains. Furthermore, the Ser-to-Ala substitution mutation reduces autophagic flux. Intriguingly, J20-S367D mice have the same Aβ pathology as J20-S367A mice, suggesting that Ser-to-Asp substitution fails to mimic the phosphorylated form, which specifically recruits AnxA2, which, in turn, interacts with Vamp8 and Stx17 to induce the fusion of lysosome–autophagosome and promote autophagy-mediated βCTF degradation. Clearly, these findings open up a novel class of therapeutics for AD: interventions that enhance PS-mediated autophagic degradation of Aβ. Autophagy is a conserved process by which intracellular organelles and protein aggregates are engulfed and degraded through a series of events, including the initiation and elongation of a precursor double-membraned autophagosome, fusion of autophagosomes with lysosomes to form autolysosomes, and degradation of engulfed materials by the lysosomes (26). Impairment in the protein degradation