LCMT-1 is an essential component of neuronal development Público

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

           Figure 2.............................................................................................................................. 18

           Figure 3.............................................................................................................................. 20

           Figure 4.............................................................................................................................. 22

           Figure 5.............................................................................................................................. 24

           Figure 6.............................................................................................................................. 27

           Figure 7.............................................................................................................................. 28

           Figure 8.............................................................................................................................. 30

           Figure 9.............................................................................................................................. 31

           Figure 10............................................................................................................................ 33

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

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

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

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

About this Honors Thesis

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience Chemistry, Biochemistry
Palavra-chave	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

Última modificação

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	LCMT-1 is an essential component of neuronal development ()	2020-04-13 19:36:30 -0400	Press to Select an action Download

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions