Filamentous deposits of hyperphosphorylated tau proteins are a major pathological hallmark of a large number of dementing disorders, such as Alzheimer's disease (AD) and frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The predominant isoform of protein phosphatase 2A (PP2A), ABaC, is present on the microtubule (MT) cytoskeleton, binds to tau, and regulates the phosphorylation state and MT binding/stabilizing activities of tau in cells. The primary goals of the proposed studies are to further characterize the structural and functional interrelationships that exist among ABaC, tau, and MTs, and address the hypothesis that their disruption promotes the accumulation of hyperphosphorylated forms of tau in all tauopathies.
The first aim will focus on establishing major properties of PP2A/tau and PP2A/MT interactions in vitro and in cells. Their functional significance for MT stability and the distribution and phosphorylation of tau proteins will then be investigated in Aim 2. Expression of PP2A or tau protein mutants, and novel phosphorylation-sensitive tau antibodies will be used to address the relevance of PP2A/tau/MT interactions in chosen neuronal and non-neuronal cellular models.
In Aim 3, the distribution of ABaC and tau proteins will be compared by immunohistochemistry in human brain regions from non-demented controls, AD, and other tauopathies, in order to assess whether changes in PP2A expression levels are associated with the presence of hyperphosphorylated tau in tau-positive lesions. In addition, biochemical methods will be used to correlate these results with the expression, activity and carboxymethylation levels of PP2A determined in the same brain regions. These studies should provide new insights into the functional role of PP2A in the regulation of tau and the MT cytoskeleton, and in the regulation of PP2A itself. Elucidating the mechanisms that govern normal tau functions and regulation is a key step towards understanding the processes that lead to the tau abnormalities, compromised MT functions, and neurodegenerative events in AD and other human tauopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018883-02
Application #
6509946
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Snyder, Stephen D
Project Start
2001-07-15
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$234,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Bottiglieri, Teodoro; Arning, Erland; Wasek, Brandi et al. (2012) Acute administration of L-DOPA induces changes in methylation metabolites, reduced protein phosphatase 2A methylation, and hyperphosphorylation of Tau protein in mouse brain. J Neurosci 32:9173-81
Sontag, Jean-Marie; Nunbhakdi-Craig, Viyada; Mitterhuber, Martina et al. (2010) Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells. J Neurochem 115:1455-65
Procaccio, Vincent; Salazar, Gloria; Ono, Shoichiro et al. (2006) A mutation of beta -actin that alters depolymerization dynamics is associated with autosomal dominant developmental malformations, deafness, and dystonia. Am J Hum Genet 78:947-60
Sontag, Estelle; Hladik, Christa; Montgomery, Lisa et al. (2004) Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis. J Neuropathol Exp Neurol 63:1080-91
Sontag, Estelle; Luangpirom, Ampa; Hladik, Christa et al. (2004) Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol 63:287-301
Wang, Ping-Yuan; Liu, Pingsheng; Weng, Jian et al. (2003) A cholesterol-regulated PP2A/HePTP complex with dual specificity ERK1/2 phosphatase activity. EMBO J 22:2658-67
Nunbhakdi-Craig, Viyada; Craig, Leonard; Machleidt, Thomas et al. (2003) Simian virus 40 small tumor antigen induces deregulation of the actin cytoskeleton and tight junctions in kidney epithelial cells. J Virol 77:2807-18
Nunbhakdi-Craig, Viyada; Machleidt, Thomas; Ogris, Egon et al. (2002) Protein phosphatase 2A associates with and regulates atypical PKC and the epithelial tight junction complex. J Cell Biol 158:967-78
Bigio, Eileen H; Hynan, L S; Sontag, E et al. (2002) Synapse loss is greater in presenile than senile onset Alzheimer disease: implications for the cognitive reserve hypothesis. Neuropathol Appl Neurobiol 28:218-27