Year

2018

Degree Name

Master of Research

Department

School of Biological Sciences

Abstract

Amyotrophic lateral sclerosis (ALS) is a complex, progressive and fatal motor neuron disease. There are currently no effective treatments for ALS. P2X7 receptor is a ligand-gated cation channel, which is activated by extracellular adenosine 5’-triphosphate (ATP) and present in the periphery and in the central nervous system (CNS). Among different factors contributing to the progression of ALS, the involvement of ATP-P2X7 signalling axis plays a role in this disease through the activation of microglia and astrocytes to promote death of motor neurons. Whilst the ectoATPase CD39, which hydrolyses extracellular ATP, is down-regulated in ALS leading to the potential accumulation of extracellular ATP and subsequent activation of the P2X7 receptor channel to promote disease. In order to understand the roles of the ATP-P2X7 signalling axis in ALS, cellular models that closely resemble ALS-associated models would be beneficial to establish. Furthermore, the use of CNS-penetrant P2X7 antagonists might further establish the role of the P2X7 receptor in ALS progression in vivo. Thus, this study aims to investigate P2X7 receptor and CD39 on murine EOC13 microglia to determine if it may serve as a suitable in vitro model of these molecules on microglia in ALS (Chapter 2). Moreover, this study aims to determine if CNS-penetrant P2X7 antagonists JNJ-47965567 ameliorates disease progression in SOD1 ALS mice (Chapter 3)...

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.