ORCID Profile
0000-0002-0306-5577
Current Organisations
The University of Edinburgh
,
University of the Sunshine Coast, Queensland
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Publisher: Elsevier BV
Date: 08-2007
Publisher: Informa UK Limited
Date: 02-01-2023
Publisher: Elsevier BV
Date: 12-2015
Publisher: Springer Science and Business Media LLC
Date: 11-02-2017
Publisher: The Company of Biologists
Date: 2017
DOI: 10.1242/DMM.029892
Abstract: Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, though it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here we generated two novel lines of mice that overexpress either 10 pure or 102 interrupted G4C2 repeats mediated by adeno-associated virus (AAV) and characterized relevant pathology and disease-related behavioral phenotypes. Similar levels of intracellular RNA foci developed in both lines of mice, but only mice expressing 102 repeats generated c9-RAN pathology, neuromuscular junction (NMJ) abnormalities, dispersal of the hippoc al CA1, enhanced apoptosis, and deficits in gait and cognition. Neither line of mice, however, showed extensive TAR DNA-binding protein 43 (TDP-43) pathology or neurodegeneration. Our data suggests that RNA foci pathology is not a good predictor of c9-RAN dipeptide formation, and that RAN dipeptides and NMJ dysfunction are drivers of c9-disease pathogenesis. These AAV-mediated models of C9orf72 ALS/FTD will be useful tools for studying disease pathophysiology and developing new therapeutic approaches.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2017
DOI: 10.1038/NCOMMS16158
Publisher: Springer Science and Business Media LLC
Date: 09-04-2015
DOI: 10.1038/NCOMMS7761
Abstract: How the brain’s antioxidant defenses adapt to changing demand is incompletely understood. Here we show that synaptic activity is coupled, via the NMDA receptor (NMDAR), to control of the glutathione antioxidant system. This tunes antioxidant capacity to reflect the elevated needs of an active neuron, guards against future increased demand and maintains redox balance in the brain. This control is mediated via a programme of gene expression changes that boosts the synthesis, recycling and utilization of glutathione, facilitating ROS detoxification and preventing Puma -dependent neuronal apoptosis. Of particular importance to the developing brain is the direct NMDAR-dependent transcriptional control of glutathione biosynthesis, disruption of which can lead to degeneration. Notably, these activity-dependent cell-autonomous mechanisms were found to cooperate with non-cell-autonomous Nrf2-driven support from astrocytes to maintain neuronal GSH levels in the face of oxidative insults. Thus, developmental NMDAR hypofunction and glutathione system deficits, separately implicated in several neurodevelopmental disorders, are mechanistically linked.
Publisher: Office of the Academic Executive Director, University of Tasmania
Date: 16-08-2023
DOI: 10.53761/1.20.6.16
Abstract: Widening participation has been a vehicle to facilitate access and support towards the successful completion of university studies for underrepresented groups who are less likely to pursue higher education. Yet, despite its widely accepted importance and adoption across countries such as Australia and the United Kingdom, studies to date remain largely fragmented – often employed through the lens of a single institution, or a particular priority group. Amidst this backdrop, universities and other higher education providers are increasingly probed as to their role in supporting social capital mobility, of which widening participation plays a vital component in delivering wider societal imperatives. In addition, the COVID-19 effect has worsened university participation and completion rates, as the global pandemic has placed vulnerable students (often those involved in widening participation initiatives) in more precocious conditions than ever before. Nevertheless, the purpose of this paper is to conduct a systematic literature review comprising 102 journal articles that derive 15 meta-themes to provide a timely introspection of widening participation, show key trends over time, and chart future areas of investigation for scholars and practitioners in this space.
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.CUB.2017.09.059
Abstract: The origins and genetic affinity of the aboriginal inhabitants of the Canary Islands, commonly known as Guanches, are poorly understood. Though radiocarbon dates on archaeological remains such as charcoal, seeds, and domestic animal bones suggest that people have inhabited the islands since the 5
Publisher: eLife Sciences Publications, Ltd
Date: 21-07-2017
DOI: 10.7554/ELIFE.17161
Abstract: Aberrant NMDA receptor (NMDAR) activity contributes to several neurological disorders, but direct antagonism is poorly tolerated therapeutically. The GluN2B cytoplasmic C-terminal domain (CTD) represents an alternative therapeutic target since it potentiates excitotoxic signaling. The key GluN2B CTD-centred event in excitotoxicity is proposed to involve its phosphorylation at Ser-1303 by Dapk1, that is blocked by a neuroprotective cell-permeable peptide mimetic of the region. Contrary to this model, we find that excitotoxicity can proceed without increased Ser-1303 phosphorylation, and is unaffected by Dapk1 deficiency in vitro or following ischemia in vivo. Pharmacological analysis of the aforementioned neuroprotective peptide revealed that it acts in a sequence-independent manner as an open-channel NMDAR antagonist at or near the Mg2+ site, due to its high net positive charge. Thus, GluN2B-driven excitotoxic signaling can proceed independently of Dapk1 or altered Ser-1303 phosphorylation.
Publisher: Elsevier BV
Date: 2018
Publisher: The Company of Biologists
Date: 2014
DOI: 10.1242/DMM.015222
Abstract: Mutations in RAB18 have been shown to cause the heterogeneous autosomal recessive disorder Warburg Micro syndrome (WARBM). Patients with WARBM present with a range of clinical symptoms including ocular and neurological abnormalities. However, the underlying cellular and molecular pathogenesis of the disorder remains unclear, largely due to the lack of any robust animal models phenocopying both ocular and neurological features of the disease. We report here the generation and characterisation of a novel Rab18 mutant mouse model of WARBM. Rab18 mutant mice are viable and fertile. They present with congenital nuclear cataracts and atonic pupils, recapitulating characteristic ocular features associated with WARBM. In addition, Rab18 mutant cells have an increase in lipid droplet size following treatment with oleic acid. Lipid droplet abnormalities are a characteristic feature of WARBM patient cells, as well as cells from patients with other neurodegenerative conditions. Neurological dysfunction is also apparent in Rab18 mutant mice, including progressive weakness of the hind limbs. We show that the neurological defects are most likely not due to gross perturbations in synaptic vesicle recycling in the central or peripheral nervous system. Rather, loss of Rab18 is associated with widespread disruption of the neuronal cytoskeleton, including abnormal accumulations of neurofilament and microtubule proteins in synaptic terminals and gross disorganisation of the cytoskeleton in peripheral nerves. Global proteomic profiling of peripheral nerve in Rab18 mutant mice reveals significant alterations in several core molecular pathways regulating cytoskeletal dynamics in neurons. The clear similarities between WARBM and the phenotype we describe indicate that the Rab18 mutant mouse provides an important platform for investigating the disease pathogenesis and therapeutic interventions.
Publisher: Wiley
Date: 17-02-2017
DOI: 10.1002/ANA.24864
Publisher: Queensland University of Technology
Date: 07-03-2019
Abstract: When is the best time to engage high school students in widening participation (WP) activities? With qualitative data from 46 university students at six Australian universities who are from low socioeconomic status (LSES) backgrounds, this study explored WP’s timeliness. It was found that a) the timing of the decision to go to university can occur at any point in compulsory schooling b) LSES students experienced the bulk of WP in senior high school, being the years after they have selected the university stream c) students in the university stream were exposed to WP activities while those in the non-university stream were excluded and d) participants recommended that WP should begin earlier and be concentrated in the lead up to the forced streaming decision that occurs in Year 10. Overall, earlier WP exposure that is synchronised with high school streaming processes would optimise WP activities aimed at increasing LSES university participation.
Publisher: Wiley
Date: 08-12-2009
DOI: 10.1111/J.1471-4159.2009.06440.X
Abstract: Cathepsin D (CTSD) deficiencies are fatal neurological diseases that in human infants and in sheep are characterized by extreme loss of neurons and myelin. To date, similar morphological evidence for myelin disruption in CTSD knockout mice has not been reported. Here, we show that CTSD deficiency leads to pronounced myelin changes in the murine brain: myelin-related proteolipid protein and myelin basic protein were both markedly reduced at postnatal day 24, and the amount of lipids characteristically high in myelin (e.g. plasmalogen-derived alkenyl chains and glycosphingolipid-derived 20- and 24-carbon acyl chains) were significantly lowered compared with controls. These changes were accompanied by ultrastructural alterations of myelin, including significant thinning of myelin sheaths. Furthermore, in CTSD knockout brains there was a pronounced accumulation of cholesteryl esters and abnormal levels of proteins related to cholesterol transport, with an increased content of apolipoprotein E and a reduced content of ATP-binding cassette transporter A1. These results provide evidence for dysmyelination and altered trafficking of cholesterol in brains of CTSD knockout mice, and warrant further studies on the role of lipid metabolism in the pathogenesis of CTSD deficiencies.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2018
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1038/MT.2014.209
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Thomas Gillingwater.