. Phosphorylated Presenilin 1 decreases β-amyloid by facilitating autophagosome-lysosome fusion. Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7148-7153. Epub 2017 May 22 PubMed.


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  1. Both these papers from the Greengard lab report on a bidirectional role of PS1 in APP processing— one through the known catalytic role in γ-secretase, and now an opposite role via the phosphorylation of the S367 residue, which is proposed to target βCTF to autophagosomal degradation, thereby reducing Aβ production. These findings support a general idea that processing and downstream signaling is finely balanced and that compensating mechanisms exist that prevent overproduction in healthy situations, which could be of therapeutic value.

    Mechanistically, the authors provide evidence that PS1 interacts with AnnexinA2, which, through binding with VAMP8, facilitates interaction with the autophagosomal SNARE syntaxin17. These data support previous reports, including from the same lab, that part of the APP proteolytic regulation goes through the autophagy route.

    Although appealing, I would remain cautious about such a mechanism, because it raises the question which pool of APP is subject to this. Generally, APP is processed at the surface and endosomal compartments, with early and late endosomes as major sites for Aβ production. Indeed, interfering with the ESCRT-dependent sorting of cargo, like APP, as shown by altering expression of vps34 (Morel et al. 2013) or CD2AP (Ubelmann et al. , 2017) the balance between amyloidogenic processing and sorting βCTF via ILV to lysosomal degradation. At least in this route, βCTF doesn’t need to encounter the autophagy route to reach lysosomes for degradation.

    I am wondering whether the authors invoke a direct sequestration of a pool of APP to initiating autophagosomes, i.e., prior to fusion with the lysosome? This might be addressed by identifying the subcellular compartments where PS1 and AnnexinA2 are thought to interact. The proximity ligation assay (PLA) data as well as pull-down indicate that this interaction is abundant; therefore it should be feasible to combine this with organelle identification. The prediction of the authors is, given the role of AnnexinA2 in autophago-lysosomal fusion, that the PLA-positive spots should be on these related organelles.

    On the other hand, it cannot be deduced from the data whether interaction occurs with the mature heterodimeric PS1 or with the full-length protein; in the latter case, the interaction should be confined to the ER-pool of PS1. This raises also another intriguing question: is this alternative function of PS1 mediated through the single protein, or through PS1 being associated within the γ-secretase complex? Further experimentation is required to characterize this interaction.

    Of note, while here phosphorylation of S367 is protective, a recent publication showed that phosphorylation at this residue (and other residues) results in a more “closed” conformation of γ-secretase and thus an increase in Aβ42/40 ratios (Maesako et al., 2017).


    . Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system. Nat Commun. 2013;4:2250. PubMed.

    . Bin1 and CD2AP polarise the endocytic generation of beta-amyloid. EMBO Rep. 2017 Jan;18(1):102-122. Epub 2016 Nov 28 PubMed.

    . Pathogenic PS1 phosphorylation at Ser367. Elife. 2017 Jan 30;6 PubMed.

    View all comments by Wim Annaert
  2. A γ-secretase-independent function of PS has been implicated in several signaling pathways (Duggan and McCarthy, 2016). Importantly, proteolytically inactive PS is biologically active in several organisms, including the moss P. patens (Khandelwal et al., 2007), in which the other γ-secretase components are not conserved. Thus, non-proteolytic function of PS in the membrane/protein trafficking might be one of the moonlighting roles of PS family proteins. This idea is also supported by biological properties of other pseudoproteases. iRhom proteins are catalytically inert rhomboids—the intramembrane cleaving serine proteases—and some of them regulate protein trafficking (Lemberg et al., 2016). In addition, proteolytically inactive DPP10 and ADAM11 regulate the subcellular localization of potassium channels (Nadal et al., 2003Kole et al., 2015). 

    Although some results are controversial, this study and another recent paper Maesako et al. (2017) reminds us that the hydrophilic loop 6 is a functionally and pathologically important domain of PS1. The primary sequences of loop 6 of PS1 and PS2 are not conserved, and several specific binding partners have been reported, indicating that the hydrophilic loop 6 is involved in PS1/PS2-specific function. In addition, Deng et al. (2006) reported that genetic ablation of exon 10 of PS1, encoding amino acids 320-377, in mice increased the Aβ42 ratio and CTF levels in the brain. In addition, deletion of exon 9-10 identified in a patient with early onset AD exacerbated the pathological effect of exon 9 deletion in cultured cells (Le Guennec et al., 2017). Thus, further precise investigation of this region could provide novel therapeutic approaches to AD.


    . Beyond γ-secretase activity: The multifunctional nature of presenilins in cell signalling pathways. Cell Signal. 2016 Jan;28(1):1-11. Epub 2015 Oct 21 PubMed.

    . Moonlighting activity of presenilin in plants is independent of gamma-secretase and evolutionarily conserved. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13337-42. PubMed.

    . Inactive rhomboid proteins: New mechanisms with implications in health and disease. Semin Cell Dev Biol. 2016 Dec;60:29-37. Epub 2016 Jul 1 PubMed.

    . The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels. Neuron. 2003 Feb 6;37(3):449-61. PubMed.

    . Selective Loss of Presynaptic Potassium Channel Clusters at the Cerebellar Basket Cell Terminal Pinceau in Adam11 Mutants Reveals Their Role in Ephaptic Control of Purkinje Cell Firing. J Neurosci. 2015 Aug 12;35(32):11433-44. PubMed.

    . Pathogenic PS1 phosphorylation at Ser367. Elife. 2017 Jan 30;6 PubMed.

    . Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology. J Neurosci. 2006 Apr 5;26(14):3845-54. PubMed.

    . Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds. Neurobiol Dis. 2017 Aug;104:97-103. Epub 2017 Apr 28 PubMed.

    View all comments by Taisuke Tomita

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  1. Does Presenilin 1 Moonlight as Autophagy Driver, Paradoxically Reducing Aβ?