Table of Contents

    Topic review


    View times: 58
    Submitted by: Cristina Fasolato


    Presenilin-2 (PS2) is one of the three proteins that are dominantly mutated in familial Alzheimer’s disease (FAD). It forms the catalytic core of the γ-secretase complex—a function shared with its homolog presenilin-1 (PS1)—the enzyme ultimately responsible of amyloid-β  (Aβ) formation. PS2 is also involved in several functions, also independently of γ-secretase activity, ranging from Ca2+ signalling to inter-organelle communication and autophagy. FAD-linked PS2 mutations impact on multiple aspects of cell and tissue physiology, including bioenergetics and brain network excitability.

    Presenilin-2 (PS2), like its homolog presenilin-1 (PS1), is a 50-kDa multi-pass membrane protein with nine helical transmembrane (TM) domains, and in humans it is encoded by a gene present on chromosome 1 (PSEN2)[1].

    1. Introduction

    Both presenilins (PSs) mainly localize to the endoplasmic reticulum (ER) and Golgi apparatus (GA) membranes but also, although less abundantly, in plasma membrane (PM) and endosomes [2]. Their mRNAs are expressed in different human and mouse tissues, with the highest levels in the hippocampus and cerebellum [3].

    2. Presenilin-2 in Physiology and Pathology

    Both PSs represent the catalytic core of the γ-secretase complex, the enzyme ultimately responsible for generation of Aβ peptides; they were both discovered in genetic analyses of families in which Alzheimer’s disease (AD) is transmitted as an autosomal dominant trait. In fact, as of now, about 300 mutations in PSEN1 and 58 mutations in PSEN2 have been described (, the majority of which are dominant, mostly missense, and have been associated with the inherited forms of the disease (familial Alzheimer’s disease (FAD)) [4][5]. Mutations in the gene for one of the substrate of the γ-secretase complex, the amyloid precursor protein (APP), are also responsible for FAD cases [6]. It has been proposed that FAD-PS mutations lead to a less precise γ-secretase cleavage of APP, in some cases decreasing the total production of Aβ but increasing the relative amount of the more amyloidogenic Aβ42 peptide, the seeding core of extracellular amyloid plaques, over the more soluble Aβ40 peptide [6].

    The γ-secretase complex is part of the family of intramembrane-cleaving proteases (I-CliPs), which perform hydrolysis of protein domains embedded in the hydrophobic environment of the membrane. The family includes SP2 metalloproteases, serine proteases of the rhomboid family, and the aspartyl proteases to which γ-secretase belongs.

    The γ-secretase has a central role in cellular biology, with about 150 different integral membrane proteins recognized as substrates [9]; the most studied are the Notch family of receptors, with a crucial role in signalling and cell differentiation, and APP [4][7] The γ-secretase complex is composed of four subunits: PS1 or PS2; nicastrin, an integral membrane protein concerned with substrate recognition and selection [8]; PS enhancer-2 (PEN-2) that stabilizes the PS complex and has a role in its endoproteolytic cleavage [9]; and anterior pharynx defective 1 (APH1), which interacts with nicastrin, providing the initial scaffold to which PS1/2 and PEN-2 are added [10]. In humans, APH1 is encoded by two paralogous genes (APH1A and APH1B), and each protein can interact with either PS, resulting in the existence of four different γ-secretase complexes that might have slightly different specificities [11]. After its enclosure within the complex, PS undergoes an endoproteolytic cleavage that produces N- and C-terminal fragments; the two fragments remain associated and represent the biologically active form of the complex, each carrying one of the two key aspartic acid residues on TM6 and TM7, respectively [12]

    PS1 and PS2 share about 66% of amino acidic sequence; one key difference is a motif in PS2 that interacts with activating protein-1 (AP-1) complexes in a phosphorylation-dependent manner and targets PS2 to the late endosome/lysosome compartment, leading to a different subcellular distribution of PS2 and perhaps to subtly different functions [13][14]. For example, it has been demonstrated that PS2-containing γ-secretase complexes are involved in the processing of premelanosome (PMEL) protein, which is involved in melanosome maturation and melanin deposition. Indeed, PS2-null zebrafish showed defects in skin pigmentation [15]. Importantly, melanosome biogenesis seems to be Ca2+-dependent[16].

    Several γ-secretase-independent functions of PSs have emerged in the recent years, enriching the overall importance of these proteins in cell biology. For example, PSs bind to glycogen synthase kinase 3β (GSK3β), a key protein of the Wnt signalling pathway, and to its substrate β-catenin, a transcription regulator [17]. The interaction of PSs with GSK3β and β-catenin is independent of γ-secretase activity [18] and influences β-catenin phosphorylation and turnover, as well as the activity of kinesin-1 and dynein and thus axonal transport of type 1 transmembrane receptors [19]. PSs have been implicated also in autophagy and protein trafficking [20].

    Last, but not least, the regulation of cellular Ca2+ homeostasis has emerged as a key PS function with relevant implications in multiple Ca2+-regulated cell processes [21][22]. FAD-linked PS2 mutations are also linked to neuronal hyperactivity [23]and alterations in spontaneous brain oscillations [24][25]. The central role played by PS2 in cellular Ca2+ homeostasis, and  brain pathophysiology has recently summarized [26][27][28].

    The entry is from 10.3390/cells9102166


    1. Suman Jayadev; James B. Leverenz; Ellen Steinbart; Justin Stahl; William Klunk; Cheng-En Yu; Thomas D. Bird; Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain 2010, 133, 1143-1154, 10.1093/brain/awq033.
    2. A. L. Brunkan; Alison M. Goate; Presenilin function and gamma-secretase activity. Journal of Neurochemistry 2005, 93, 769-792, 10.1111/j.1471-4159.2005.03099.x.
    3. M K Lee; H H Slunt; L J Martin; G Thinakaran; G Kim; S E Gandy; M Seeger; E Koo; Donald L. Price; S S Sisodia; et al. Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues.. The Journal of Neuroscience 1996, 16, 7513-7525, .
    4. Lucía Chávez-Gutiérrez; Leen Bammens; Iryna Benilova; Annelies Vandersteen; Manasi Benurwar; Marianne Borgers; Sam Lismont; Lujia Zhou; Simon Van Cleynenbreugel; Hermann Esselmann; et al. The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. The EMBO Journal 2012, 31, 2261-2274, 10.1038/emboj.2012.79.
    5. Lucía Chávez-Gutiérrez; Maria Szaruga; Mechanisms of neurodegeneration — Insights from familial Alzheimer’s disease. Seminars in Cell & Developmental Biology 2020, 105, 75-85, 10.1016/j.semcdb.2020.03.005.
    6. Justin M. Long; David M. Holtzman; Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell 2019, 179, 312-339, 10.1016/j.cell.2019.09.001.
    7. Gökhan Güner; Stefan F. Lichtenthaler; The substrate repertoire of γ-secretase/presenilin. Seminars in Cell & Developmental Biology 2020, 105, 27-42, 10.1016/j.semcdb.2020.05.019.
    8. David M. Bolduc; Daniel R. Montagna; Yongli Gu; Dennis J. Selkoe; Michael S. Wolfe; Nicastrin functions to sterically hinder γ-secretase–substrate interactions driven by substrate transmembrane domain. Proceedings of the National Academy of Sciences 2015, 113, E509-E518, 10.1073/pnas.1512952113.
    9. Oliver Holmes; Swetha Paturi; Dennis J. Selkoe; Michael S. Wolfe; Pen-2 Is Essential for γ-Secretase Complex Stability and Trafficking but Partially Dispensable for Endoproteolysis. Biochemistry 2014, 53, 4393-4406, 10.1021/bi500489j.
    10. Raphaëlle Pardossi-Piquard; Seung-Pil Yang; Soshi Kanemoto; Yongjun Gu; Fusheng Chen; Christopher Böhm; Jean Sevalle; Tong Li; Philip C. Wong; Frédéric Checler; et al. APH1 Polar Transmembrane Residues Regulate the Assembly and Activity of Presenilin Complexes. Journal of Biological Chemistry 2009, 284, 16298-16307, 10.1074/jbc.m109.000067.
    11. Lutgarde Serneels; Jérôme Van Biervliet; Katleen Craessaerts; Tim Dejaegere; Katrien Horré; Tine Van Houtvin; Hermann Esselmann; Sabine Paul; Martin K. Schäfer; Oksana Berezovska; et al. -Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer's Disease. Science 2009, 324, 639-642, 10.1126/science.1171176.
    12. Michael S. Wolfe; Substrate recognition and processing by γ-secretase. Biochimica et Biophysica Acta (BBA) - Biomembranes 2020, 1862, 183016, 10.1016/j.bbamem.2019.07.004.
    13. Ragna Sannerud; Cary Esselens; Paulina Ejsmont; Rafael Mattera; Leila Rochin; Arun Kumar Tharkeshwar; Greet De Baets; Veerle De Wever; Roger Habets; Veerle Baert; et al. Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool. Cell 2016, 166, 193-208, 10.1016/j.cell.2016.05.020.
    14. Xavier Meckler; Frédéric Checler; Presenilin 1 and Presenilin 2 Target γ-Secretase Complexes to Distinct Cellular Compartments. Journal of Biological Chemistry 2016, 291, 12821-12837, 10.1074/jbc.m115.708297.
    15. Haowei Jiang; Morgan Newman; Michael Lardelli; The zebrafish orthologue of familial Alzheimer’s disease gene PRESENILIN 2 is required for normal adult melanotic skin pigmentation. PLOS ONE 2018, 13, e0206155, 10.1371/journal.pone.0206155.
    16. Zhao Zhang; Juanjuan Gong; Elena V. Sviderskaya; Aihua Wei; Wei Li; Mitochondrial NCKX5 regulates melanosomal biogenesis and pigment production. Journal of Cell Science 2019, 132, jcs232009, 10.1242/jcs.232009.
    17. Zhuohua Zhang; Henrike Hartmann; Viet Minh Do; Dorothee Abramowski; Christine Sturchler-Pierrat; Matthias Staufenbiel; Bernd Sommer; Marc Van De Wetering; Hans Clevers; Paul Saftig; et al. Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature 1998, 395, 698-702, 10.1038/27208.
    18. Salvador Soriano; David E. Kang; Maofu Fu; Richard Pestell; Nathalie Chevallier; Hui Zheng; Edward H. Koo; Presenilin 1 Negatively Regulates β-Catenin/T Cell Factor/Lymphoid Enhancer Factor-1 Signaling Independently of β-Amyloid Precursor Protein and Notch Processing. The Journal of Cell Biology 2001, 152, 785-794, 10.1083/jcb.152.4.785.
    19. Kunsang Dolma; Gary J. Iacobucci; Kan Hong Zheng; Jayasha Shandilya; Eneda Toska; Joseph A White; Elizabeth Spina; Shermali Gunawardena; Presenilin influences glycogen synthase kinase-3 β (GSK-3β) for kinesin-1 and dynein function during axonal transport. Human Molecular Genetics 2013, 23, 1121-1133, 10.1093/hmg/ddt505.
    20. Gael Barthet; Julie Dunys; Zhiping Shao; Zhao Xuan; Yimin Ren; Jindong Xu; Nicolas Arbez; Gweltas Mauger; Julien Bruban; Anastasios Georgakopoulos; et al. Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors. Neurobiology of Aging 2013, 34, 499-510, 10.1016/j.neurobiolaging.2012.02.024.
    21. Frank M. LaFerla; Calcium dyshomeostasis and intracellular signalling in alzheimer's disease. Nature Reviews Neuroscience 2002, 3, 862-872, 10.1038/nrn960.
    22. Elisa Greotti; Paola Capitanio; Andrea Wong; Tullio Pozzan; Paola Pizzo; Diana Pendin; Familial Alzheimer’s disease-linked presenilin mutants and intracellular Ca2+ handling: A single-organelle, FRET-based analysis. Cell Calcium 2019, 79, 44-56, 10.1016/j.ceca.2019.02.005.
    23. Maulilio J. Kipanyula; Laura Contreras; Enrico Zampese; Cristian Lazzari; Andrea K. C. Wong; Paola Pizzo; Cristina Fasolato; Tullio Pozzan; Ca2+dysregulation in neurons from transgenic mice expressing mutant presenilin 2. Aging Cell 2012, 11, 885-893, 10.1111/j.1474-9726.2012.00858.x.
    24. Roberto Fontana; Mario Agostini; Emanuele Murana; Mufti Mahmud; Elena Scremin; Maria Rubega; Giovanni Sparacino; Stefano Vassanelli; Cristina Fasolato; Early hippocampal hyperexcitability in PS2APP mice: role of mutant PS2 and APP. Neurobiology of Aging 2017, 50, 64-76, 10.1016/j.neurobiolaging.2016.10.027.
    25. Alessandro Leparulo; Mufti Mahmud; Elena Scremin; Tullio Pozzan; Stefano Vassanelli; Cristina Fasolato; Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease. Cells 2019, 9, 54, 10.3390/cells9010054.
    26. R. Scott Duncan; Bo Song; Peter Koulen; Presenilins as Drug Targets for Alzheimer’s Disease—Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development. International Journal of Molecular Sciences 2018, 19, 1621, 10.3390/ijms19061621.
    27. Luisa Galla; Nelly Redolfi; Tullio Pozzan; Paola Pizzo; Elisa Greotti; Intracellular Calcium Dysregulation by the Alzheimer’s Disease-Linked Protein Presenilin 2. International Journal of Molecular Sciences 2020, 21, 770, 10.3390/ijms21030770.
    28. Paola Pizzo; Emy Basso; Riccardo Filadi; Elisa Greotti; Alessandro Leparulo; Diana Pendin; Nelly Redolfi; Michela Rossini; Nicola Vajente; Tullio Pozzan; et al. Presenilin-2 and Calcium Handling: Molecules, Organelles, Cells and Brain Networks. Cells 2020, 9, 2166, 10.3390/cells9102166.