Associate Professor Estelle Sontag
Honorary Associate Professor
School of Biomedical Sciences and Pharmacy (Medical Biochemistry)
- Email:estelle.sontag@newcastle.edu.au
- Phone:(02) 4921 6239
Career Summary
Biography
After obtaining her PhD in Neuroscience from the University Louis-Pasteur in Strasbourg in France, Dr. Estelle Sontag undertook postdoctoral training at UT Southwestern Medical Center at Dallas, TX, a top-ranked Medical school in the USA. During this time, she started investigating the role of protein phosphatase 2A (PP2A) in the regulation of cell growth and viral cell transformation, and was promoted to Instructor in the Department of Pharmacology led by Nobel Laureate A. Gilman. She then moved to the Department of Pathology/Neuropathology division at UT Southwestern, where she was promoted to Associate Professor. Over the years, she has led a NIH-funded research group dedicated to further studying the regulation and role of PP2A in signal transduction, cell adhesion and neurodegeneration. A particular focus of her research has been to investigate the role of PP2A in Alzheimer’s disease, the most prevalent dementia, and participate to neuropathological studies as Senior Investigator of the NIH-funded UT Southwestern Alzheimer’s Disease Center. In 2009, she relocated to the University of Newcastle to further pursue her research on PP2A and Alzheimer’s disease.
Dr. Estelle Sontag is currently a Member of the Australian Research Council (ARC) College of Experts.
Research Expertise:
Dr. Estelle Sontag is a senior biochemist, molecular and cell biologist and neuroscientist, and group leader of the "PP2A signalling in cell transformation and neurodegeneration" laboratory. She is an internationally recognised specialist in the field of protein phosphatase 2A (PP2A), having made several significant contributions to the field by unveiling the role of this major enzyme in signal transduction, viral-mediated cell transformation and Alzheimer's disease pathogenesis (h-index 34; >4700 citations; 4 papers in Faculty1000).
PP2A signalling in cell transformation and neurodegeneration
Dr. Estelle Sontag: Group leader
Dr. Jean-Marie Sontag: Co-group leader
Regulation of virtually all cellular processes involves reversible protein phosphorylation, which is mediated via the concerted action of protein kinases and phosphatases. One of the major and most conserved cellular phosphatase enzymes is protein phosphatase 2A (PP2A). Notably, many pathogens target PP2A to deregulate cell function. PP2A dysfunction is involved in a variety of diseases, including cancer and Alzheimer's disease, the most prevalent dementia.
Over the years, our work has provided novel fundamental insights into the role of PP2A in the regulation of cell growth and adhesion, and viral-mediated cell transformation (Cell, 1993; EMBO J., 1997; J. Cell Biol., 2002; J Virol 2003). We have also identified PP2A as a key regulator of tau, a hallmark protein involved in Alzheimer's disease, and cytoskeletal dynamics (J Cell Biol 1995; Neuron 1996; J. Biol. Chem. 1999, 2012, 2013; J. Neurochem 2007, 2010; FEBS Lett. 2017). Our group has done pioneering work showing that PP2A methylation becomes downregulated in Alzheimer's disease, and following alterations in folate and homocysteine metabolism, resulting in PP2A dysfunction and subsequent neurodegeneration (JNEN 2004; J. Neurosci. 2007, 2008, 2012; Frontiers in Aging Neurosci. 2014; Frontiers in Molecular Neuroscience, 2014; Proc Natl Acad Sci USA.2016; Journal of Alzheimer disease 2018).
Currently, our research work is focused on further elucidating PP2A regulatory mechanisms and assessing their functional significance for both neuronal and epithelial cell homeostasis. We strive to understand how deregulation of these fundamental mechanisms leads to cell transformation and neurodegeneration, so that they could be exploited to develop novel therapeutic strategies for Alzheimer's disease and cancer. Our work is performed in collaboration with several national and international laboratories.
Dr. Sontag is regularly invited as speaker at national and international meetings. She is also a member of international journal editorial and grant reviewing boards.
Teaching Expertise
Currently: Lecturer and Coordinator: HUBS2209 Human Cell Biology and Cancer; Lecturer: Joint Medical Program year 1; HUBS3403 Neuroscience
2009-2017: Lecturer: MEDI1012 Introduction to Medical Science; MEDI1015 Medical Science 1; MEDI2012 Medical Science 2; MEDI2014 Medical Science 3; MEDI3017 Chronic Diseases and Sub-Speciality Clinical Practice 1; MEDI3018 Chronic Diseases and Sub-Speciality Clinical Practice 2;HUBS3409 Projects in Biomedical Science- Review of literature projects. Lecturer and tutor: PHAR6123 Human Genomics and Biomolecular Analysis for Pharmacy; HUBS2207 Human Metabolic and Nutritional BiochemistryLecturer
1998-2009: Member, ACGME-accredited UT Southwestern Department of Pathology Neuropathology Fellowship training program (Director: Dr. CL. White III)
Administrative Expertise
2019:Deputy Director, Preclinical Neurobiology Research Hub Leader, Priority Research Centre for Brain and Mental Health Research (CBMHR), University of Newcastle
2019-present: School of Biomedical Sciences & Pharmacy Research Committee, University of Newcastle
2016-present: Student Academic Conduct Officer, School of Biomedical Sciences & Pharmacy, University of Newcastle
2015-2018: Member, Joint Medical Program, Teaching and Learning Committee, University of Newcastle
2011-2012: School of Biomedical Sciences & Pharmacy Executive Committee, Research Committee, University of Newcastle
2004-2009: Member, Postdoctoral Advisory Committee of UT Southwestern Graduate School of Biomedical Sciences program (ranked among top 20 in the US)
Qualifications
- Doctor of Philosophy, Louis Pasteur University - Strasbourg
Keywords
- Alzheimer's disease
- Cancer cell biology
- Cell adhesion
- Cell biology
- Cell biology
- Cell transformation
- Cytoskeleton
- DNA tumor viruses
- Enzymes
- Folate
- Homocysteine
- Metabolism
- Methylation
- Molecular and cell biology
- Neuroscience
- PP2A
- Phosphatase
- Protein biochemistry
- Signal transduction
- Tau
Languages
- French (Fluent)
Fields of Research
Code | Description | Percentage |
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310111 | Signal transduction | 100 |
Professional Experience
UON Appointment
Title | Organisation / Department |
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Associate Professor | University of Newcastle School of Biomedical Sciences and Pharmacy Australia |
Academic appointment
Dates | Title | Organisation / Department |
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1/9/2003 - 28/2/2009 | Associate Professor of Pathology | UT Southwestern Medical Center Pathology/ Division of Neuropathology United States |
Membership
Dates | Title | Organisation / Department |
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1/1/2016 - 30/12/2030 | Membership- International Society for Neurochemistry (ISN) | The International Society for Neurochemistry Australia |
1/1/2015 - 12/12/2021 | Editorial Board- Frontiers in Cell and development Biology | https://Frontiers in Cell and Developmental biology Switzerland |
1/1/2015 - 30/12/2030 | American Society for Biochemistry and cell Biology (ASBMB) | American Society for Biochemistry and Molecular Biology United States |
1/1/2010 - | Membership - Australian Neuroscience Society | Australian Neuroscience Society (ANS) Australia |
1/1/2006 - 31/12/2020 | Editorial Board - Journal of Neuropathology and Experimental Neurology | Journal of Neuropathology and Experimental Neurology Australia |
1/1/2004 - | Membership - Society for Neuroscience | Society for Neuroscience United States |
1/1/2003 - | Membership - Society for Microbiology | Society for Microbiology Australia |
1/1/1996 - | Membership - American Society for Cell Biology | American Society for Cell Biology United States |
Invitations
Speaker
Year | Title / Rationale |
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2015 |
New insights into the regulation of tau by protein phosphatase 2A Conference: ISN-APSN-ANS joint meeting 2015, Cairns, Australia |
Publications
For publications that are currently unpublished or in-press, details are shown in italics.
Chapter (1 outputs)
Year | Citation | Altmetrics | Link |
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2008 | Sontag JM, Sontag E, 'PP2A: Multitasking and making decisions in cell growth', Protein Research Progress, Nova Science Publishers, Hauppauge, New York, United States of America 17-61 (2008) [B1] |
Journal article (68 outputs)
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2023 |
van Hummel A, Taleski G, Sontag JM, Feiten AF, Ke YD, Ittner LM, Sontag E, 'Methyl donor supplementation reduces phospho-Tau, Fyn and demethylated protein phosphatase 2A levels and mitigates learning and motor deficits in a mouse model of tauopathy', Neuropathology and Applied Neurobiology, 49 (2023) [C1] Background: Reduced folate status and elevated levels of circulating homocysteine are modifiable risk factors for cognitive decline and dementia. Disturbances in one-carbon metabo... [more] Background: Reduced folate status and elevated levels of circulating homocysteine are modifiable risk factors for cognitive decline and dementia. Disturbances in one-carbon metabolism are associated with the pathological accumulation of phosphorylated tau, a hallmark feature of prevalent dementia, including Alzheimer's disease and subgroups of frontotemporal dementia. Methods: Here, using transgenic TAU58/2 mouse models of human tauopathy, we tested whether dietary supplementation with L-methylfolate (the active folate form), choline and betaine can reduce tau phosphorylation and associated behavioural phenotypes. Results: TAU58/2 mice fed with the methyl donor-enriched diet showed reduced phosphorylation of tau at the pathological S202 (CP13) and S396/S404 (PHF-1) epitopes and alleviation of associated motor and learning deficits. Compared with mice on the control diet, the decrease in cortical phosphorylated tau levels in mice fed with the methyl donor-enriched diet was associated with enhanced methylation of protein phosphatase 2A, the major brain tau Ser/Thr phosphatase. It also correlated with a reduction in protein levels of Fyn, a tau tyrosine kinase that plays a central role in mediating pathological tau-induced neurodegeneration. Conversely, Fyn expression levels were increased in mice with deficiencies in folate metabolism. Conclusions: Our findings provide the first experimental evidence that boosting one-carbon metabolism with L-methylfolate, choline and betaine can mitigate key pathological, learning and motor deficits in a tauopathy mouse model. They give support to using a combination of methyl donors as a preventive or disease-modifying strategy for tauopathies.
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2022 |
Sontag J-M, Schuhmacher D, Taleski G, Jordan A, Khan S, Hoffman A, et al., 'A new paradigm for regulation of protein phosphatase 2A function via Src and Fyn kinase-mediated tyrosine phosphorylation.', J Biol Chem, 298 102248 (2022) [C1]
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2022 |
Schuhmacher D, Sontag JM, Sontag E, 'A Novel Role of PP2A Methylation in the Regulation of Tight Junction Assembly and Integrity', Frontiers in Cell and Developmental Biology, 10 (2022) [C1] Tight junctions (TJs) are multiprotein complexes essential for cell polarity and the barrier function of epithelia. The major signaling molecule, protein serine/threonine phosphat... [more] Tight junctions (TJs) are multiprotein complexes essential for cell polarity and the barrier function of epithelia. The major signaling molecule, protein serine/threonine phosphatase 2A (PP2A), interacts with the TJ and modulates the phosphorylation state of TJ proteins. An important PP2A regulatory mechanism involves leucine carboxyl methyltransferase-1 (LCMT1)-dependent methylation and protein phosphatase methylesterase-1 (PME1)-mediated demethylation of its catalytic subunit on Leu309. Here, using MDCK cells, we show that overexpression of LCMT1, which enhances cellular PP2A methylation, inhibits TJ formation, induces TJ ruffling, and decreases TJ barrier function. Conversely, overexpression of PME1 accelerates TJ assembly and enhances TJ barrier function. PME1-dependent PP2A demethylation increases during early Ca2+-dependent junctional assembly. Inhibition of endogenous PME1 delays the initial Ca2+-mediated redistribution of TJ proteins to cell-cell contacts and affects TJ morphology and barrier function. Manipulating one-carbon metabolism modulates TJ assembly, at least in part by affecting PP2A methylation state. The integrity of PP2A methylation is critical for proper targeting of PP2A to the TJ. It is necessary for PP2A complex formation with the TJ proteins, occludin and ZO-1, and proteins of the PAR complex, Par3 and atypical protein kinase C ¿ (aPKC¿), which play a key role in development of cell polarity. Expression of a methylation incompetent PP2A mutant induces defects in TJ assembly and barrier function. aPKC¿-mediated Par3 phosphorylation is also required for targeting of the PP2A ABaC holoenzyme to the TJ. Our findings provide the first evidence for a role of LCMT1, PME1 and PP2A methylation/demethylation processes in modulating TJ assembly and functional integrity. They also position PP2A at the interface of one-carbon metabolism and the regulation of key TJ and polarity proteins that become deregulated in many human diseases.
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2021 |
Taleski G, Schuhmacher D, Su H, Sontag JM, Sontag E, 'Disturbances in PP2A methylation and one-carbon metabolism compromise Fyn distribution, neuritogenesis, and APP regulation', Journal of Biological Chemistry, 296 (2021) [C1] The nonreceptor protein tyrosine kinase Fyn and protein Ser/Thr phosphatase 2A (PP2A) are major multifunctional signaling molecules. Deregulation of Fyn and altered PP2A methylati... [more] The nonreceptor protein tyrosine kinase Fyn and protein Ser/Thr phosphatase 2A (PP2A) are major multifunctional signaling molecules. Deregulation of Fyn and altered PP2A methylation are implicated in cancer and Alzheimer s disease (AD). Here, we tested the hypothesis that the methylation state of PP2A catalytic subunit, which influences PP2A subunit composition and substrate specificity, can affect Fyn regulation and function. Using Neuro-2a (N2a) neuroblastoma cell models, we first show that methylated PP2A holoenzymes containing the B? subunit coimmunoprecipitate and copurify with Fyn in membrane rafts. PP2A methylation status regulates Fyn distribution and Fyn-dependent neuritogenesis, likely in part by affecting actin dynamics. A methylation-incompetent PP2A mutant fails to interact with Fyn. It perturbs the normal partitioning of Fyn and amyloid precursor protein (APP) in membrane microdomains, which governs Fyn function and APP processing. This correlates with enhanced amyloidogenic cleavage of APP, a hallmark of AD pathogenesis. Conversely, enhanced PP2A methylation promotes the nonamyloidogenic cleavage of APP in a Fyn-dependent manner. Disturbances in one-carbon metabolic pathways that control cellular methylation are associated with AD and cancer. Notably, they induce a parallel loss of membrane-Associated methylated PP2A and Fyn enzymes in N2a cells and acute mouse brain slices. One-carbon metabolism also modulates Fyn-dependent process outgrowth in N2a cells. Thus, our findings identify a novel methylation-dependent PP2A/Fyn signaling module. They highlight the underestimated importance of cross talks between essential metabolic pathways and signaling scaffolds that are involved in normal cell homeostasis and currently being targeted for cancer and AD treatment.
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2020 |
Woods JJ, Skelding KA, Martin KL, Aryal R, Sontag E, Johnstone DM, et al., 'Assessment of evidence for or against contributions of Chlamydia pneumoniae infections to Alzheimer's disease etiology', Brain, Behavior, and Immunity, 83 22-32 (2020) [C1] Alzheimer's disease, the most common form of dementia, was first formally described in 1907 yet its etiology has remained elusive. Recent proposals that Aß peptide may be par... [more] Alzheimer's disease, the most common form of dementia, was first formally described in 1907 yet its etiology has remained elusive. Recent proposals that Aß peptide may be part of the brain immune response have revived longstanding contention about the possibility of causal relationships between brain pathogens and Alzheimer's disease. Research has focused on infectious pathogens that may colonize the brain such as herpes simplex type I. Some researchers have proposed the respiratory bacteria Chlamydia pneumoniae may also be implicated in Alzheimer's disease, however this remains controversial. This review aims to provide a balanced overview of the current evidence and its limitations and future approaches that may resolve controversies. We discuss the evidence from in vitro, animal and human studies proposed to implicate Chlamydia pneumoniae in Alzheimer's disease and other neurological conditions, the potential mechanisms by which the bacterium may contribute to pathogenesis and limitations of previous studies that may explain the inconsistencies in the literature.
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2020 |
Frohner IE, Mudrak I, Schüchner S, Anrather D, Hartl M, Sontag JM, et al., 'PP2Ac Phospho-Tyr307 Antibodies Are Not Specific for this Modification but Are Sensitive to Other PP2Ac Modifications Including Leu309 Methylation', Cell Reports, 30 3171-3182.e6 (2020) [C1]
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2019 |
Schuhmacher D, Sontag J-M, Sontag E, 'Protein Phosphatase 2A: More Than a Passenger in the Regulation of Epithelial Cell-Cell Junctions', FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 7 (2019) [C1]
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2019 |
Ahmed AF, de Bock CE, Sontag E, Hondermarck H, Lincz LF, Thorne RF, 'FAT1 cadherin controls neuritogenesis during NTera2 cell differentiation', Biochemical and Biophysical Research Communications, 514 625-631 (2019) [C1]
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2018 |
Hoffman A, Taleski G, Qian H, Wasek B, Arning E, Bottiglieri T, et al., 'Methylenetetrahydrofolate Reductase Deficiency Deregulates Regional Brain Amyloid-ß Protein Precursor Expression and Phosphorylation Levels', Journal of Alzheimer's Disease, 64 223-237 (2018) [C1] Deregulation of the amyloid-ß protein precursor (AßPP) plays a critical role in the neurodegenerative cascade of Alzheimer's disease (AD). Significantly, common functional po... [more] Deregulation of the amyloid-ß protein precursor (AßPP) plays a critical role in the neurodegenerative cascade of Alzheimer's disease (AD). Significantly, common functional polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene are a risk factor for the development of late-onset AD. Reduced MTHFR activity is associated with alterations in folate and homocysteine metabolism. Here, we first show that in young MTHFR knockout mice, mild and severe MTHFR deficiency markedly increase cortical and hippocampal AßPP phosphorylation at the regulatory Thr668 site. However, the hippocampus is especially vulnerable to the effects of aging and mild MTHFR deficiency. Notably, the effects of severe MTHFR deficiency in young mice are recapitulated by prolonged dietary folate deficiency in old mice, which leads to regional brain accumulation of cystathionine due to impaired methylation of homocysteine. The incremental AßPP phosphorylation at Thr668 mediated by severe genetic-or diet-induced impairment of the folate cycle correlates with enhanced accumulation of demethylated protein phosphatase 2A (PP2A), and activation of glycogen synthase kinase-3ß (GSK-3ß). Lastly, we show that severe disturbances in folate metabolism can also affect AßPP expression levels in a brain region specific manner. Together our findings identify a novel link between genetic MTHFR deficiency, activation of GSK-3ß, demethylation of PP2A, and enhanced phosphorylation of AßPP at Thr668, which is known to critically influence neuronal AßPP function and pathological amyloidogenic processing. Deregulation of AßPP provides a novel mechanism by which common human MTHFR polymorphisms may interact with dietary folate deficiency to alter neuronal homeostasis and increase the risk for sporadic AD.
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2018 |
Taleski G, Sontag E, 'Protein phosphatase 2A and tau: an orchestrated Pas de Deux ', FEBS Letters, 592 1079-1095 (2018) [C1] The neuronal microtubule-associated protein tau serves a critical role in regulating axonal microtubule dynamics to support neuronal and synaptic functions. Furthermore, it contri... [more] The neuronal microtubule-associated protein tau serves a critical role in regulating axonal microtubule dynamics to support neuronal and synaptic functions. Furthermore, it contributes to glutamatergic regulation and synaptic plasticity. Emerging evidence also suggests that tau serves as a signaling scaffold. Tau function and subcellular localization are tightly regulated, in part, by the orchestrated interplay between phosphorylation and dephosphorylation events. Significantly, protein phosphatase type 2A (PP2A), encompassing the regulatory PPP2R2A (or Ba) subunit, is a major brain heterotrimeric enzyme and the primary tau Ser/Thr phosphatase in vivo. Herein, we closely examine how the intimate and compartmentalized interactions between PP2A and tau regulate tau phosphorylation and function, and play an essential role in neuronal homeostasis. We also review evidence supporting a strong link between deregulation of tau¿PP2A functional interactions and the molecular underpinnings of various neurodegenerative diseases collectively called tauopathies. Lastly, we discuss the opportunities and associated challenges in more specifically targeting PP2A¿tau interactions for drug development for tauopathies.
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2017 |
Hoffman A, Taleski G, Sontag E, 'The protein serine/threonine phosphatases PP2A, PP1 and calcineurin: A triple threat in the regulation of the neuronal cytoskeleton', Molecular and Cellular Neuroscience, 84 119-131 (2017) [C1]
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2016 |
Nicholls RE, Sontag JM, Zhang H, Staniszewski A, Yan S, Kim CY, et al., 'PP2A methylation controls sensitivity and resistance to ß-amyloid-induced cognitive and electrophysiological impairments', Proceedings of the National Academy of Sciences of the United States of America, 113 3347-3352 (2016) [C1] Elevated levels of the ß-amyloid peptide (Aß) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer's disease (AD). Protein phosphatase 2A (... [more] Elevated levels of the ß-amyloid peptide (Aß) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer's disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxylmethyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Aß exposure. We found that PME-1 overexpression enhanced these impairments, whereas LCMT-1 overexpression protected against Aß-induced impairments. Neither transgene affected Aß production or the electrophysiological response to low concentrations of Aß, suggesting that these manipulations selectively affect the pathological response to elevated Aß levels. Together these data identify a molecular mechanism linking PP2A to the development of AD-related cognitive impairments that might be therapeutically exploited to target selectively the pathological effects caused by elevated Aß levels in AD patients.
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2015 |
Ahmed AF, De Bock CE, Lincz LF, Pundavela J, Zouikr I, Sontag E, et al., 'FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation', Cellular and Molecular Life Sciences, 72 4653-4669 (2015) [C1] The Hippo pathway is emerging as a critical nexus that balances self-renewal of progenitors against differentiation; however, upstream elements in vertebrate Hippo signalling are ... [more] The Hippo pathway is emerging as a critical nexus that balances self-renewal of progenitors against differentiation; however, upstream elements in vertebrate Hippo signalling are poorly understood. High expression of Fat1 cadherin within the developing neuroepithelium and the manifestation of severe neurological phenotypes in Fat1-knockout mice suggest roles in neurogenesis. Using the SH-SY5Y model of neuronal differentiation and employing gene silencing techniques, we show that FAT1 acts to control neurite outgrowth, also driving cells towards terminal differentiation via inhibitory effects on proliferation. FAT1 actions were shown to be mediated through Hippo signalling where it activated core Hippo kinase components and antagonised functions of the Hippo effector TAZ. Suppression of FAT1 promoted the nucleocytoplasmic shuttling of TAZ leading to enhanced transcription of the Hippo target gene CTGF together with accompanying increases in nuclear levels of Smad3. Silencing of TAZ reversed the effects of FAT1 depletion thus connecting inactivation of TAZ-TGFbeta signalling with Hippo signalling mediated through FAT1. These findings establish FAT1 as a new upstream Hippo element regulating early stages of differentiation in neuronal cells.
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2014 |
Sontag J, Sontag E, 'Protein phosphatase 2A dysfunction in Alzheimer s disease', Frontiers in Molecular Neuroscience, 7 1 (2014) [C1]
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2014 |
Sontag JM, Wasek B, Taleski G, Smith J, Arning E, Sontag E, Bottiglieri T, 'Altered protein phosphatase 2A methylation and Tau phosphorylation in the young and aged brain of methylenetetrahydrofolate reductase (MTHFR) deficient mice', Frontiers in Aging Neuroscience, 6 (2014) [C1] Common functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in folate and homocysteine metabolism, influence risk for a variety of comple... [more] Common functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in folate and homocysteine metabolism, influence risk for a variety of complex disorders, including developmental, vascular, and neurological diseases. MTHFR deficiency is associated with elevation of homocysteine levels and alterations in the methylation cycle. Here, using young and aged Mthfr knockout mouse models, we show that mild MTHFR deficiency can lead to brain-region specific impairment of the methylation of Ser/Thr protein phosphatase 2A (PP2A). Relative to wild-type controls, decreased expression levels of PP2A and leucine carboxyl methyltransferase (LCMT1) were primarily observed in the hippocampus and cerebellum, and to a lesser extent in the cortex of young null Mthfr-/-and aged heterozygous Mthfr+/- mice. A marked down regulation of LCMT1 correlated with the loss of PP2A/Ba holoenzymes. Dietary folate deficiency significantly decreased LCMT1, methylated PP2A and PP2A/Ba levels in all brain regions examined from aged Mthfr+/+ mice, and further exacerbated the regional effects of MTHFR deficiency in aged Mthfr+/-mice. In turn, the down regulation of PP2A/Ba was associated with enhanced phosphorylation of Tau, a neuropathological hallmark of Alzheimer's disease (AD). Our findings identify hypomethylation of PP2A enzymes, which are major CNS phosphatases, as a novel mechanism by which MTHFR deficiency and Mthfr gene-diet interactions could lead to disruption of neuronal homeostasis, and increase the risk for a variety of neuropsychiatric disorders, including age-related diseases like sporadic AD. © 2014 Sontag, Wasek, Taleski, Smith, Arning, Sontag and Bottiglieri.
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2014 |
Sontag J-M, Sontag E, Tesone-Coelho C, Takemori H, Zwiller J, Dietrich J-B, 'Cocaine Regulates the Salt-Inducible Kinase (SIK1) by Inducing Protein Phosphatase-2A Expression in Rat Brain', Journal of Drug and Alcohol Research, 3 1-7 (2014) [C1]
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2013 |
Sontag JM, Nunbhakdi-Craig V, Sontag E, 'Leucine carboxyl methyltransferase 1 (LCMT1)-dependent methylation regulates the association of protein phosphatase 2A and Tau protein with plasma membrane microdomains in neuroblastoma cells', Journal of Biological Chemistry, 288 27396-27405 (2013) [C1] Down-regulation of protein phosphatase 2A (PP2A) methylation occurs in Alzheimer disease (AD). However, the regulation of PP2A methylation remains poorly understood. We have repor... [more] Down-regulation of protein phosphatase 2A (PP2A) methylation occurs in Alzheimer disease (AD). However, the regulation of PP2A methylation remains poorly understood. We have reported that altered leucine carboxyl methyltransferase (LCMT1)-dependent PP2A methylation is associated with down-regulation of PP2A holoenzymes containing the Ba subunit (PP2A/Ba) and subsequent accumulation of phosphorylated Tau in N2a cells, in vivo and in AD. Here, we show that pools of LCMT1, methylated PP2A, and PP2A/Ba are co-enriched in cholesterol-rich plasma membrane microdomains/rafts purified from N2a cells. In contrast, demethylated PP2A is preferentially distributed in non-rafts wherein small amounts of the PP2A methylesterase PME-1 are exclusively present. A methylation-incompetent PP2A mutant is excluded from rafts. Enhanced methylation of PP2A promotes the association of PP2A and Tau with the plasma membrane. Altered PP2A methylation following expression of a catalytically inactive LCMT1 mutant, knockdown of LCMT1, or alterations in one-carbon metabolism all result in a loss of plasma membrane-associated PP2A and Tau in N2a cells. This correlates with accumulation of soluble phosphorylated Tau, a hallmark of AD and other tauopathies. Thus, our findings reveal a distinct compartmentalization of PP2A and PP2A regulatory enzymes in plasma membrane microdomains and identify a novel methylation-dependent mechanism involved in modulating the targeting of PP2A, and its substrate Tau, to the plasma membrane. We propose that alterations in the membrane localization of PP2A and Tau following down-regulation of LCMT1 may lead to PP2A and Tau dysfunction in AD. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.
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2010 |
Sontag J-M, Nunbhakdi-Craig V, Mitterhuber M, Ogris E, Sontag EF, 'Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells', Journal of Neurochemistry, 115 1455-1465 (2010) [C1]
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Show 65 more journal articles |
Conference (32 outputs)
Year | Citation | Altmetrics | Link | ||
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2017 | Hoffman A, Sontag J-M, Wasek B, Bottiglieri T, Sontag E, 'Brain region specific alterations in the transcription factor CREB in folate and MTHFR deficient mice.', Sydney (2017) | ||||
2017 | Sontag E, Sontag J-M, Gomez RJ, Hoffman A, Taleski G, Mazalouskas MD, et al., 'AT THE CROSSROADS BETWEEN TYR AND SER/THR SIGNALING: A NEW PARADIGM IN THE REGULATION OF PP2A BY SRC KINASE', FASEB JOURNAL, Chicago, IL (2017) | ||||
2016 | Hoffman A, Sontag J-M, Wasek B, Bottiglieri T, Sontag E, 'Brain region specific alterations in the transcription factor CREB in folate and MTHFR deficient mice', Hobart (2016) | ||||
2015 | Sontag E, Sontag J-M, 'New insights into the regulation of tau by protein phosphatase 2A', JOURNAL OF NEUROCHEMISTRY, Cairns, AUSTRALIA (2015) [E3] | ||||
2015 | Hoffman A, Sontag J-M, Sontag E, 'PP2A methylation plays a critical role in cAMP/PKA-dependent regulation of tau and neurite outgrowth', JOURNAL OF NEUROCHEMISTRY, Cairns, AUSTRALIA (2015) [E3] | ||||
2015 | Sontag J-M, Hoffman A, Wadzinski BE, Sontag E, 'Novel mechanisms of C-SRC kinase-dependent regulation of PP2A: implications for tauopathies', JOURNAL OF NEUROCHEMISTRY, Cairns, AUSTRALIA (2015) [E3] | ||||
2014 | Sontag E, 'Alterations in PP2A and tau in mouse models of MTHFR deficiency', -, UNSW, Sydney, Australia (2014) [E3] | ||||
2014 | Sontag E, Hoffman A, Sontag JM, Bottiglieri T, 'Signal transduction by PP2A: Regulating the regulator.', -, Canberra (2014) [E3] | ||||
2014 | Sontag JM, Wasek B, Taleski T, Smith J, Arning E, Sontag E, Bottiglieri T, 'Methylation of protein phosphatase 2A and phosphorylation of Tau protein in brain tissue from methylenetetrahydrofolate reductase deficient mice', -, Steamboat Springs, Colorado (2014) [E3] | ||||
2013 | Sontag JM, Arning E, Numbhakdi-Craig V, Wasek B, Bottiglieri T, Sontag E, 'Regulation of PP2A methylation by genetic/drug/dietary interactions Implication for the treatment of neurodegenerative disorders', -, Melbourne, Australia (2013) [E3] | ||||
2013 | Sontag EFG, 'Regional Effects of Acute L-DOPA Administration on Monoamines, Gamma-aminobutyric Acid and Acetylcholine Levels in the Mouse Brain', -, Florence, Italy (2013) [E3] | ||||
2013 |
Ahmed AF, De Bock CE, Sontag E, Hondermarck H, Thorne RF, 'The functional role of Fat1 cadherin in the differentiation and proliferation of SH-SY5Y neuroblastoma cells', -, Pokolbin, NSW, Australia (2013) [E3]
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2013 | Sontag E, Sontag JM, Bottiglieri T, Arancio O, Nichollls R, 'Significance of protein phosphatase 2A in Alzheimer s disease', 7th Alzheimer's & Parkinson's Disease Symposium, Queensland Brain Institute (QBI), The University of Queensland, Australia (2013) [E3] | ||||
2013 | Nicholls RE, Sontag JM, Zhang H, Staniszewski A, Woodruff CM, Yim M, et al., 'The role of PP2A methylation in beta-amyloid sensitivity and resistance', The 11th International Conference on Alzheimer s and Parkinson s Diseases, Florence, Italy (2013) [E3] | ||||
2012 | Nicholls RE, Sontag J-M, Zhang H, Staniszewski A, Woodruff CM, Yim M, et al., 'The role of PP2A methylation in beta-amyliod sensitivity and resistance', Neuroscience 2012. Abstracts, New Orleans (2012) [E3] | ||||
2012 | Sontag J-M, Nunbhakdi-Craig V, Bottiglieri T, Sontag EF, 'Regulation of PP2A methylation - Implications for neurogenerative disorders', Phosphates in Human Disease. Meeting Programme & Abstract Book, Melbourne, Vic (2012) [E3] | ||||
2012 | Sontag EF, Sontag J-M, 'New insights into the regulation and role of PP2A methylation in Alzheimer disease', 2012 FASEB Science Research Conferences. Protein Phosphates, Snowmass, CO (2012) [E3] | ||||
2012 | Arning E, Nunbhakdi-Craig V, Wasek B, Bottiglieri T, Sontag EF, Sontag J-M, 'Regulation of PP2A methylation by genetic/drug/dietary interactions - Implications for the treatment of neurodegenerative disorders', 2012 FASEB Science Research Conferences. Protein Phosphates, Snowmass, CO (2012) [E3] | ||||
2011 | Wasek B, Erland A, Sontag J-M, Sontag EF, Bottiglieri T, 'The effect of microwave irradiation on methylation metabolites in folate deficient mouse brain tissue', Abstracts. 8th International Conference on Homocysteine Metabolism, Lisboa, Portugal (2011) [E3] | ||||
2011 | Arning E, Wasek B, Williams M, Sontag EF, Bottiglieri T, 'L-dopa treatment reduces plasma concentrations of pyridoxal phosphate (vitamin b6) and decreases brain serotonin metabolism in the mouse: Implications for vitamin b6 dependent enzymes', Abstracts. The 10th International Conference on Alzheimer's and Parkinson's Diseases, Barcelona, Spain (2011) [E3] | ||||
2011 | Sontag J-M, Nunbhakdi-Craig V, Sontag EF, 'Protein phosphatase 2A methylation plays a critical role in neurite outgrowth', Oral abstracts. Australian Neuroscience Society Annual Meeting, Auckland, NZ (2011) [E3] | ||||
2011 | Sontag J-M, Nunbhakdi-Craig V, Sontag EF, 'A novel role for protein phosphatase 2A methylation in neuritogenesis', The 11th Hunter Meeting, Hunter Valley, NSW (2011) [E3] | ||||
2010 | Sontag EF, Sontag J-M, Arning E, Nunbhakdi-Craig V, Wasek B, Bottiglieri T, 'Role of PP2A methylation in neurodegeneration', International Symposium on Protein Phosphorylation in Neurodegenerative Diseases: Abstracts, Valencia, Spain (2010) [E3] | ||||
2010 | Sontag J-M, Nunbhakdi-Craig V, Sontag EF, 'Protein phosphatase 2A methylation plays a critical role in neurite outgrowth', Neuroscience 2010: Final Program, San Diego, CA (2010) [E3] | ||||
2009 |
Sontag EF, 'Role of PP2A methylation pathways in tau regulation', Alzheimer's and Dementia, Vienna, Austria (2009) [E3]
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2009 | Bottiglieri T, Arning E, Wasek B, Sontag J-M, Sontag EF, 'L-dopa induces changes in methylation metabolites, PP2A demethylation and hyper-phosphorylation of Tau protein in mouse brain', 7th International Conference on Homocysteine Metabolism: Abstract Book, Prague, Czech Republic (2009) [E3] | ||||
Show 29 more conferences |
Grants and Funding
Summary
Number of grants | 11 |
---|---|
Total funding | $992,877 |
Click on a grant title below to expand the full details for that specific grant.
20172 grants / $323,600
Towards the development of new therapeutic interventions for Alzheimer's Disease$295,600
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Associate Professor Estelle Sontag, Doctor Jean-Marie Sontag |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2017 |
Funding Finish | 2022 |
GNo | G1700055 |
Type Of Funding | C3300 – Aust Philanthropy |
Category | 3300 |
UON | Y |
Targeting LCMT1-mediated neuroprotective mechanisms in Alzheimer disease$28,000
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Doctor Jean-Marie Sontag, Associate Professor Estelle Sontag |
Scheme | Project Grant |
Role | Investigator |
Funding Start | 2017 |
Funding Finish | 2017 |
GNo | G1700002 |
Type Of Funding | C3300 – Aust Philanthropy |
Category | 3300 |
UON | Y |
20152 grants / $60,700
Can methylfolate improve the treatment of Alzheimer's disease patients, alone or in combination with the drug, Memantine$60,000
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Associate Professor Estelle Sontag, Doctor Jean-Marie Sontag |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2015 |
Funding Finish | 2016 |
GNo | G1501390 |
Type Of Funding | Grant - Aust Non Government |
Category | 3AFG |
UON | Y |
International Society for Neurochemistry - Biennial meeting and Advanced School, Fizroy Island and Cairns AUS, 19-27 August 2015$700
Funding body: University of Newcastle - Faculty of Health and Medicine
Funding body | University of Newcastle - Faculty of Health and Medicine |
---|---|
Project Team | Associate Professor Estelle Sontag |
Scheme | Travel Grant |
Role | Lead |
Funding Start | 2015 |
Funding Finish | 2015 |
GNo | G1500686 |
Type Of Funding | Internal |
Category | INTE |
UON | Y |
20143 grants / $93,014
JuLI Stage $71,674
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Professor Pradeep Tanwar, Professor Eileen McLaughlin, Emeritus Professor Robin Callister, Professor Xu Dong Zhang, Professor Murray Cairns, Professor Brett Nixon, Professor Hubert Hondermarck, Associate Professor Phillip Dickson, Associate Professor Nikki Verrills, Professor Matt Dun, Doctor Jessie Sutherland, Doctor Janani Kumar, Professor Jay Horvat, Associate Professor Susan Hua, Prof LIZ Milward, Associate Professor Estelle Sontag, Professor Dirk Van Helden, Doctor Janet Bristow, Doctor Jean-Marie Sontag |
Scheme | Equipment Grant |
Role | Investigator |
Funding Start | 2014 |
Funding Finish | 2014 |
GNo | G1500860 |
Type Of Funding | Other Public Sector - Commonwealth |
Category | 2OPC |
UON | Y |
Can dietary folate supplementation slow down Alzheimer’s Disease?$20,000
Funding body: Hunter Medical Research Institute
Funding body | Hunter Medical Research Institute |
---|---|
Project Team | Doctor Jean-Marie Sontag, Associate Professor Estelle Sontag |
Scheme | Project Grant |
Role | Investigator |
Funding Start | 2014 |
Funding Finish | 2014 |
GNo | G1401436 |
Type Of Funding | Grant - Aust Non Government |
Category | 3AFG |
UON | Y |
ComBio2014, Canberra Australia, 28 September - 2 October 2014$1,340
Funding body: University of Newcastle - Faculty of Health and Medicine
Funding body | University of Newcastle - Faculty of Health and Medicine |
---|---|
Project Team | Associate Professor Estelle Sontag |
Scheme | Travel Grant |
Role | Lead |
Funding Start | 2014 |
Funding Finish | 2014 |
GNo | G1400731 |
Type Of Funding | Internal |
Category | INTE |
UON | Y |
20132 grants / $59,596
Leica TP 1020 Automatic Tissue Processor for histology applications$35,000
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Professor Pradeep Tanwar, Professor Eileen McLaughlin, Professor Xu Dong Zhang, Conjoint Professor Robert Callister, Associate Professor Phillip Dickson, Professor Hubert Hondermarck, Doctor Jean-Marie Sontag, Professor Dirk Van Helden, Associate Professor Doug Smith, Associate Professor Phil Jobling, Associate Professor Estelle Sontag, Associate Professor Paul Tooney, Associate Professor Susan Hua, Doctor Janet Bristow, Professor Jay Horvat, Prof LIZ Milward, Professor Adam McCluskey, Professor Brett Nixon, Associate Professor Rebecca Lim, Professor Alan Brichta |
Scheme | Equipment Grant |
Role | Investigator |
Funding Start | 2013 |
Funding Finish | 2013 |
GNo | G1201185 |
Type Of Funding | Other Public Sector - Commonwealth |
Category | 2OPC |
UON | Y |
Ultra-Low Temperature Cryogenic Freezer$24,596
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Doctor Jude Weidenhofer, Doctor Rick Thorne, Associate Professor Kathryn Skelding, Associate Professor Nikki Verrills, Professor Pradeep Tanwar, Associate Professor Phillip Dickson, Professor Murray Cairns, Professor Hubert Hondermarck, Professor Xu Dong Zhang, Associate Professor Estelle Sontag, Doctor Chen Chen Jiang, Prof LIZ Milward, Doctor Jean-Marie Sontag, Associate Professor Paul Tooney, Doctor Severine Roselli Dayas, Professor Matt Dun, Professor Chris Dayas, Doctor Lin Kooi Ong, Professor Dirk Van Helden, Mr Ben Copeland, Doctor Gabrielle Briggs, Emeritus Professor Leonie Ashman, Emeritus Professor John Rostas |
Scheme | Equipment Grant |
Role | Investigator |
Funding Start | 2013 |
Funding Finish | 2013 |
GNo | G1201189 |
Type Of Funding | Other Public Sector - Commonwealth |
Category | 2OPC |
UON | Y |
20121 grants / $1,500
2012 FASEB Science Research Conferences - Protein phosphatases, Snowmass Colorado, 15 - 20 July 2012$1,500
Funding body: University of Newcastle - Faculty of Health and Medicine
Funding body | University of Newcastle - Faculty of Health and Medicine |
---|---|
Project Team | Associate Professor Estelle Sontag |
Scheme | Travel Grant |
Role | Lead |
Funding Start | 2012 |
Funding Finish | 2013 |
GNo | G1200536 |
Type Of Funding | Internal |
Category | INTE |
UON | Y |
20111 grants / $454,467
Protein Phosphatase 2A methylation: Regulation and functional significance for tauopathies$454,467
Funding body: NHMRC (National Health & Medical Research Council)
Funding body | NHMRC (National Health & Medical Research Council) |
---|---|
Project Team | Associate Professor Estelle Sontag, Doctor Jean-Marie Sontag |
Scheme | Project Grant |
Role | Lead |
Funding Start | 2011 |
Funding Finish | 2013 |
GNo | G1000241 |
Type Of Funding | Aust Competitive - Commonwealth |
Category | 1CS |
UON | Y |
Research Supervision
Number of supervisions
Past Supervision
Year | Level of Study | Research Title | Program | Supervisor Type |
---|---|---|---|---|
2022 | PhD | Investigating the Processes of Age-Related Inflammation in the Central Nervous System | PhD (Anatomy), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2022 | PhD | Novel Insights into Protein Phosphatase 2A Regulation and Function in Cell Adhesion | PhD (Medical Biochemistry), College of Health, Medicine and Wellbeing, The University of Newcastle | Principal Supervisor |
2021 | PhD | Does Brain Iron Elevation Modify the Course of Functional and Pathological Changes in Mouse Models of Alzheimer's Disease Amyloidosis and Parkinson's Disease? | PhD (Medical Genetics), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2021 | PhD | Studies of Respiratory Chlamydia Infections in Mouse Models of Chlamydia Infection and Alzheimer’s Disease | PhD (Medical Genetics), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2021 | PhD | The Deregulation of Fyn Kinase in Alzheimer's Disease | PhD (Medical Biochemistry), College of Health, Medicine and Wellbeing, The University of Newcastle | Principal Supervisor |
2020 | PhD | The Relationship of Iron and Amyloid: Insights from a New Mouse Model of Iron Loading and Amyloidosis | PhD (Medical Genetics), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
2019 | PhD | The Role of Protein Phosphatase 2A in Alzheimer’s Disease Pathogenesis | PhD (Medical Biochemistry), College of Health, Medicine and Wellbeing, The University of Newcastle | Principal Supervisor |
2015 | PhD | Role of FAT1 Cadherin in Neuronal Differentiation | PhD (Medical Biochemistry), College of Health, Medicine and Wellbeing, The University of Newcastle | Co-Supervisor |
Associate Professor Estelle Sontag
Position
Honorary Associate Professor
(02) 4921 5018
School of Biomedical Sciences and Pharmacy
College of Health, Medicine and Wellbeing
Focus area
Medical Biochemistry
Contact Details
estelle.sontag@newcastle.edu.au | |
Phone | (02) 4921 6239 |
Fax | (02) 4921 7903 |
Link | Research Networks |
Office
Room | LS3-34 |
---|---|
Building | Life Sciences |
Location | Callaghan University Drive Callaghan, NSW 2308 Australia |