Role of Protein Phosphatase 2A in Regulating Tau Phosphorylation During Mouse Embryogenesis Open Access
Evans II, Paul Robert (2010)
Published
Abstract
Abstract
Decreased Protein Phosphatase 2A Methylation Results in Elevated
Tau Phosphorylation
During Mouse Embryogenesis
By Paul R. Evans
Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine
phosphatase with
implications in many cellular processes including cell cycle and
tau phosphorylation
regulation. PP2A is composed of a structural A subunit, catalytic C
subunit, and a
variable regulatory B subunit. We have previously shown that in
mammalian cells,
leucine carboxyl methyltransferase-1 (LCMT-1) must methylate PP2A C
for holoenzyme
formation with Bα subunits, and a complete knockout of LCMT-1
in mice results in
embryonic lethality (Lee and Pallas, 2007). Further, the BαAC
heterotrimer is the main
tau phosphatase, accounting for over 70% of total tau phosphatase
activity (Liu et al.,
2005). Elevated tau phosphorylation levels are a hallmark of
tauopathies, human
neurodegenerative disease associated with tau neurofibrillary
degeneration and dementia.
Given that BαAC heterotrimers only form after LCMT-1
methylates PP2A and this
isoform is responsible for the majority of tau phosphatase
activity, we predict that a
knockout of LCMT-1 in an in vivo mammalian mouse model will result
in elevated tau
phosphorylation by synergizing with a tau P301L mutant transgene.
We tested our
hypothesis using quantitative immunoblotting and
immunohistochemistry with day 12.5
mouse embryos. We report that a full, but not partial, knockout of
LCMT-1 results in
extremely downregulated LCMT-1 expression, PP2A methylation, and
increased 3R and
4R tau phosphorylation.
Table of Contents
Table of Contents
Introduction 1
Methods 8
Results 15
Discussion 20
Figures 23
Figure 1: LCMT-1 Structure and Regulation
Figure 2: Embryo Phenotypes and Genotyping
Figure 3: LCMT-1 Expression is Down-regulated in Hemizygous and
Homozygous LCMT-1 Knockout Mice
Figure 4: Loss of one LCMT-1 Allele Does Not Result in a
Significant Decrease in PP2A C Methylation
Figure 5: Three Repeat Tau (3R) Isoform Phosphorylation is
Increased in LCMT-1 Homozygous Knockout Mouse Embryos
Figure 6: Four Repeat Tau (4R) Isoform Phosphorylation is Increased
in LCMT-1 Homozygous Knockout Mouse Embryos
Figure 7: Demethylated PP2A Catalytic Subunit Immunohistochemical
Staining is Increased in Homozygous Knockout LCMT-1 Embryos
Figure 8: Three Repeat Tau Immunohistochemical Staining
Table 1: Timed Mating Genotype Frequency Analysis
Literature Cited 32
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