Research in our laboratory is focused on understanding the role of the Ser/Thr protein phosphatase 2A (PP2A) in Alzheimer disease (AD)pathogenesis, and the regulation of cell adhesion and transformation.
1) Role of PP2A in AD: The major project of our laboratory is to test the hypothesis that deregulation of PP2A methylation contributes to AD pathogenesis. Central neuropathological features of AD are the accumulation of numerous amyloid beta-containing senile plaques and phosphorylated tau-rich neurofibrillary tangles in the hippocampus and neocortex. We have found that PP2A methylation and expression become altered in AD-affected brain regions. Recently, we have shown that decreased PP2A methylation is associated with an increase in the phosphorylation levels of tau and altered processing of the amyloid precursor protein. Using mouse and neuronal cell models, we are striving to elucidate the mechanisms by which neuronal PP2A dysfunction could promote abnormal accumulation of tau and amyloid-beta aggregates, disruption of the microtubule cytoskeleton, and compromized neuronal plasticity in AD. In this context, we are currently investigating how alterations in homocysteine metabolism affect the regulation of PP2A methylation and its neuronal targets.
2) Role of PP2A in cell adhesion and transformation Remarkably, PP2A is a target of the DNA tumor virus, SV40. During SV40 infection of the host cell, SV40 small tumor antigen (small t) forms a complex with endogenous PP2A, resulting in deregulation of PP2A activity. Consequently, major PP2A-dependent signaling pathways that control cell growth, adhesion and survival become altered. Our long-term goal is to identify the intracellular targets of PP2A/SV40 small t that contribute to cell transformation in both cellular and mouse models. We are especially interested in investigating how defects in PP2A targeting and functional specificity influence the regulation of intracellular adhesion (tight junctions and remodeling of the actin cytoskeleton) in epithelial cells.
RESEARCH INTERESTS
Alzheimer disease and tauopathies
Cell transformation by PP2A/SV40 small t
Homocysteine and folate metabolism
Regulation and function of PP2A methylation
Role of PP2A in cell adhesion
RECENT PUBLICATIONS
Sontag E, Nunbhakdi-Craig V, Sontag JM, Diaz-Arrastia R, Ogris E, Dayal S, Lentz SR, Arning E, Bottiglieri T., "Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation." J Neurosci., 27(11):2751-9., March 2007
Nunbhakdi-Craig V, Schuechner S, Sontag JM, Montgomery L, Pallas DC, Juno C, Mudrak I, Ogris E, Sontag E., "Expression of protein phosphatase 2A mutants and silencing of the regulatory B alpha subunit induce a selective loss of acetylated and detyrosinated microtubules." J Neurochem., 101(4)::959-71, May 2007
Sontag JM, Sontag E., "Regulation of cell adhesion by PP2A and SV40 small tumor antigen: an important link to cell transformation." Cell Mol Life Sci., 63(24)::2979-91, December 2006
Sontag E, Hladik C, Montgomery L, Luangpirom A, Mudrak I, Ogris E, White CL 3rd., "Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis." J Neuropathol Exp Neurol., 63(10)::1080-91., October 2004
Procaccio V, Salazar G, Ono S, Styers ML, Gearing M, Davila A, Jimenez R, Juncos J, Gutekunst CA, Meroni G, Fontanella B, Sontag E, Sontag JM, Faundez V, Wainer BH., "A mutation of beta -actin that alters depolymerization dynamics is associated with autosomal dominant developmental malformations, deafness, and dystonia." Am J Hum Genet. 78(6):947-60., 78(6)::947-60., June 2006
SIGNIFICANT PUBLICATIONS
Sontag E, Fedorov S, Kamibayashi C, Robbins D, Cobb M, Mumby M, "The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the MAP kinase pathway and induces cell proliferation." Cell, 75(5):887-897, December 1993
Sontag E, Nunbhakdi-Craig V, Lee G, Bloom GS, Mumby MC, "Regulation of the phosphorylation state and microtubule-binding activity of tau by protein phosphatase 2A." Neuron, 17(6):1201-1207, December 1996
Sontag E, Nunbhakdi-Craig V, Bloom GS, Mumby MC, "A novel pool of protein phosphatase 2A is associated with microtubules and is regulated during the cell-cycle." J. Cell. Biol., 128(6):1131-1144, March 1995
Sontag E, Sontag JM, Garcia A, "Protein phosphatase 2A is a critical regulator of protein kinase C z signaling targeted by SV40 small t to promote cell growth and NF-kB activation." Embo J., 16(18):5662-5671, September 1997
Nunbhakdi-Craig V, Machleidt T, Ogris E, Bellotto D, White III CL, Sontag E, "PP2A associates with and regulates atypical PKC and the epithelial tight junction complex." J. Cell. Biol., 158(5):967-978, September 2002
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