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Calcium signalling in TDP-43 models of motor neurone disease and frontotemporal dementia

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posted on 28.03.2022, 16:22 authored by Gabriella Chan
Motor neurone disease (MND) and frontotemporal dementia (FTD) are terminal neurodegenerative diseases, with rapid disease progression. Clinically, patients present with overlapping symptoms, and the diseases share underlying genetic features and pathophysiology. Notably, pathological changes in neuronal excitability and calcium dynamics have been reported in disease. Furthermore, these signalling changes are implicated in neuronal death present in motor neurone disease and frontotemporal dementia. However, the current literature is unclear as to the nature of these excitability changes, with some studies suggesting that hyperexcitability leads to excitotoxicity, while others suggest that hypoexcitable neurons are most vulnerable to neurodegeneration. The present study presents two complementary models for investigation of calcium signalling changes in disease and reports on preliminary findings as proof of concept. Firstly, signalling changes were identified in an in vitro model of disease, by co-transducing primary hippocampal neurons with variants of the disease related protein TDP-43 together with the fluorescent calcium sensor jGCaMP7f. Calcium activity was then recorded in a TDP-43 mouse model of disease using the Miniscope miniaturised microscope system. This Miniscope application in a neurodegenerative disease mouse model is the first of its kind in this field. In these models TDP-43 expression reduced calcium response during spontaneous neuronal spiking activity, while increasing signalling synchronicity. These changes occurred through increased sensitivity to neuronal stimulation as well as decreased response to repeat stimulation, suggesting a complex and nuanced relationship between excitability and neurodegeneration. Together, these models provide a promising platform for further study of MND and FTD pathomechanisms.

History

Table of Contents

1 Introduction -- 2 Methods -- 3 Results -- 4 Discussion.

Notes

Theoretical thesis. Bibliography: pages 51-58

Awarding Institution

Macquarie University

Degree Type

Thesis MRes

Degree

MRes, Macquarie University, Faculty of Medical and Health Sciences, Department of Biomedical Sciences

Department, Centre or School

Department of Biomedical Sciences

Year of Award

2019

Principal Supervisor

Yazi Ke

Additional Supervisor 1

Annika van Hummel

Rights

Copyright Gabriella Chan 2019 Copyright disclaimer: http://mq.edu.au/library/copyright

Language

English

Extent

1 online resource (x, 66 pages) illustrations

Former Identifiers

mq:72085 http://hdl.handle.net/1959.14/1281231