Florey Department of Neuroscience and Mental Health - Research Publications
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ItemNo Preview AvailableRetinal alpha-synuclein accumulation correlates with retinal dysfunction and structural thinning in the A53T mouse model of Parkinson's disease(FRONTIERS MEDIA SA, 2023-05-05)Abnormal alpha-synuclein (α-SYN) protein deposition has long been recognized as one of the pathological hallmarks of Parkinson's disease's (PD). This study considers the potential utility of PD retinal biomarkers by investigating retinal changes in a well characterized PD model of α-SYN overexpression and how these correspond to the presence of retinal α-SYN. Transgenic A53T homozygous (HOM) mice overexpressing human α-SYN and wildtype (WT) control littermates were assessed at 4, 6, and 14 months of age (male and female, n = 15-29 per group). In vivo retinal function (electroretinography, ERG) and structure (optical coherence tomography, OCT) were recorded, and retinal immunohistochemistry and western blot assays were performed to examine retinal α-SYN and tyrosine hydroxylase. Compared to WT controls, A53T mice exhibited reduced light-adapted (cone photoreceptor and bipolar cell amplitude, p < 0.0001) ERG responses and outer retinal thinning (outer plexiform layer, outer nuclear layer, p < 0.0001) which correlated with elevated levels of α-SYN. These retinal signatures provide a high throughput means to study α-SYN induced neurodegeneration and may be useful in vivo endpoints for PD drug discovery.
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ItemCharacterization of retinal function and structure in the MPTP murine model of Parkinson's disease(NATURE PORTFOLIO, 2022-05-09)In addition to well characterized motor symptoms, visual disturbances are increasingly recognized as an early manifestation in Parkinson's disease (PD). A better understanding of the mechanisms underlying these changes would facilitate the development of vision tests which can be used as preclinical biomarkers to support the development of novel therapeutics for PD. This study aims to characterize the retinal phenotype of a mouse model of dopaminergic dysfunction and to examine whether these changes are reversible with levodopa treatment. We use a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD to characterize the neurotoxic effects of MPTP on in vivo retinal function (electroretinography, ERG), retinal structure (optical coherence tomography, OCT) and retinal dopaminergic cell number (tyrosine hydroxylase immunohistochemistry, IHC) at two time points (21 and 45 days) post MPTP model induction. We also investigate the effect of levodopa (L-DOPA) as a proof-of-principle chronic intervention against MPTP-induced changes in the retina. We show that MPTP decreases dopaminergic amacrine cell number (9%, p < 0.05) and that a component of the ERG that involves these cells, in particular oscillatory potential (OP) peak timing, was significantly delayed at Day 45 (7-13%, p < 0.01). This functional deficit was paralleled by outer plexiform layer (OPL) thinning (p < 0.05). L-DOPA treatment ameliorated oscillatory potential deficits (7-13%, p < 0.001) in MPTP animals. Our data suggest that the MPTP toxin slows the timing of inner retinal feedback circuits related to retinal dopaminergic pathways which mirrors findings from humans with PD. It also indicates that the MPTP model causes structural thinning of the outer retinal layer on OCT imaging that is not ameliorated with L-DOPA treatment. Together, these non-invasive measures serve as effective biomarkers for PD diagnosis as well as for quantifying the effect of therapy.
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ItemEffects of Excess Iron on the Retina: Insights From Clinical Cases and Animal Models of Iron Disorders(FRONTIERS MEDIA SA, 2022-02-03)Iron plays an important role in a wide range of metabolic pathways that are important for neuronal health. Excessive levels of iron, however, can promote toxicity and cell death. An example of an iron overload disorder is hemochromatosis (HH) which is a genetic disorder of iron metabolism in which the body's ability to regulate iron absorption is altered, resulting in iron build-up and injury in several organs. The retina was traditionally assumed to be protected from high levels of systemic iron overload by the blood-retina barrier. However, recent data shows that expression of genes that are associated with HH can disrupt retinal iron metabolism. Thus, the effects of iron overload on the retina have become an area of research interest, as excessively high levels of iron are implicated in several retinal disorders, most notably age-related macular degeneration. This review is an effort to highlight risk factors for excessive levels of systemic iron build-up in the retina and its potential impact on the eye health. Information is integrated across clinical and preclinical animal studies to provide insights into the effects of systemic iron loading on the retina.
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ItemTherapeutic applications of chelating drugs in iron metabolic disorders of the brain and retina(WILEY, 2020-10)Iron is essential for normal cellular function, however, excessive accumulation of iron in neural tissue has been implicated in both cortical and retinal diseases. The exact role of iron in the pathogenesis of neurodegenerative disorders remains incompletely understood. However, iron-induced damage to the brain and retina is often attributed to the redox ability of iron to generate dangerous free radicals, which exacerbates local oxidative stress and neuronal damage. Iron chelators are compounds designed to scavenge labile iron, aiding to regulate iron bioavailability. Recently there has been growing interest in the application of chelating agents for treatment of diseases including neurodegenerative conditions, characterized by increased oxidative stress. This article reviews both clinical and preclinical evidence relating to the effectiveness of iron chelation therapy in conditions of iron dyshomeostasis linked to neurodegeneration in the brain and retina. The limitations as well as future opportunities iron chelation therapy are discussed.