LCMT-1 is an essential component of neuronal development Open Access

Abstract

Protein phosphatase 2A (PP2A) is an important ubiquitous heterotrimeric protein phosphatase that participates in many important biochemical processes and pathways by regulating the phosphorylation state of numerous substrates. Global knockout (KO) of the gene encoding leucine carboxyl methyltransferase-1 (LCMT-1), a methyltransferase that regulates the stable formation of a subset of PP2A heterotrimers, results in late gestational embryonic lethality in mice [Lee & Pallas, 2018]. The neuronal consequences of LCMT-1 loss have only begun to be investigated, as have its potential impacts on the development of Alzheimer’s Disease (AD) pathology. In this study, we find tau hyperphosphorylation at important AD-correlated sites in global Lcmt-1 KO embryo brains. We also find that cultured hippocampal neurons from global Lcmt-1 KO embryos display stunted neurite outgrowth and abnormal neuronal polarity. Further, using a nestin-Cre-mediated neuronal-conditional Lcmt-1 knockout (cKO) mouse model, we find that neuronal loss of LCMT-1 results in perinatal lethality on average 22 hours after birth, likely due at least in part to an inability to feed. In P0 Lcmt-1 cKO pups, we also find evidence for hyperphosphorylation of tau at the Tau-1 antibody epitope and an increase in amount and possibly phosphorylation of an unknown isoform or truncated form of tau. Finally, using a neuronal YFP-expressing mouse model, we find that Lcmt-1 cKO hippocampal CA pyramidal cell layer neurons are reduced in number, and consistent with this, there is an apparent thinning of these cell layers. Thus, LCMT-1 has critical roles in neuronal development and in prevention of AD-related changes in tau phosphorylation.

Table of Contents

Introduction..................................................................................................................................... 1

Materials and Methods................................................................................................................... 3

Results........................................................................................................................................... 14

           Figure 1.............................................................................................................................. 16

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           Figure 11............................................................................................................................ 35

Discussion...................................................................................................................................... 36

References..................................................................................................................................... 45

Supplemental Figures.................................................................................................................... 49

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience Chemistry, Biochemistry
Keyword	nervous system development LCMT-1 PP2A hippocampus Alzheimer's Disease tau
Committee Chair / Thesis Advisor	David C. Pallas, Emory University
Committee Members	Arthur W. English, Emory University Anita H. Corbett, Emory University

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