Pathology - Theses
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ItemCuproenzyme dysfunction in the pathogenesis of amyotrophic lateral sclerosis and multiple sclerosis( 2016)Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the selective death of motor neurons within the spinal cord and brain. Although the aetiology of the disease is not well understood, inherited genetic mutations account for a small proportion of cases, with Cu,Zn-superoxide dismutase (SOD1) mutations being the most extensively studied. Effective treatment options for ALS do not exist, however, pre-clinical outcomes indicate that therapeutically modulating copper bioavailability in the central nervous system (CNS) may be a feasible treatment strategy for ALS. Therefore, the initial objective of this study was to investigate the significance of copper dyshomeostasis in the progression of a mutant SOD1 mouse model of ALS. We hypothesised that age-related changes to cuproenzymes progress with disease symptoms in SOD1G37R mice compared to age-matched non-transgenic littermates and mice overexpressing wild-type human SOD1. To test this hypothesis, locomotor performance was assessed to track disease progression, then CNS and peripheral tissues were collected at distinct stages of disease for biochemical analyses. Data presented in Chapter 3 provide evidence for copper malfunction in the CNS of ALS mice and indicate that copper malfunction is an early feature of the disease which worsens as symptoms progress. Specifically, a disconnect exists between the abundance and copper-dependent activity of cuproenzymes SOD1 and ceruloplasmin. Next, the therapeutic significance of these changes to SOD1 and ceruloplasmin were assessed. In Chapter 4, data show that overexpressing CTR1 or treating ALS model mice with the copper compound CuII(atsm) extends survival and improves copper bioavailability to SOD1 and ceruloplasmin in the CNS. To ascertain the relevance of outcomes in a broader disease context, we next assessed human cases of sporadic ALS. Data presented in Chapter 5 show that SOD1 and ceruloplasmin dysfunction detected in mice is also evident in sporadic ALS. Significantly, changes to ceruloplasmin are associated with changes to iron homeostasis, where diminished copper- dependent ceruloplasmin activity may contribute to iron overload in the ALS-affected motor cortex and decreased transferrin bound iron in the cerebrospinal fluid. As such, we propose that changes to copper-dependent ceruloplasmin activity in ALS may be the mechanistic basis for two ALS biomarkers and represent the first biochemical evidence for the feasibility of treating ALS, including sporadic ALS, by therapeutically improving copper bioavailability to CNS cuproenzymes. Multiple sclerosis (MS) is a disease characterised by CNS demyelination, with evidence suggesting a link between demyelination and limited copper bioavailability. This is supported by data presented in Chapter 7 from both ALS model mice and MS-affected CNS tissue. We also show that changes to copper, SOD1, ceruloplasmin and myelin-associated proteins are common to ALS and MS, and that modulating copper bioavailability may provide a therapeutic intervention. Overall, data presented in this thesis indicate that: copper malfunction is a feature of ALS and MS; copper malfunction evident in sporadic cases of ALS are recapitulated in mutant SOD1 mouse models of familial ALS; and perturbations to the copper-dependent ceruloplasmin activity may be important to iron accumulation in the ALS-affected motor cortex. The therapeutic implications of these observations are discussed.
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ItemIroning out the involvement of tau protein in neurodegenerative diseases( 2012)Tau protein has been extensively implicated in Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative diseases which exhibit tau depositions, termed tauopathies. Brain iron accumulation is a cooccurred pathological feature of many tauopathies and hypothesized to contribute to neurodegeneration by engendering oxidative stress. It is currently unknown what, if any, link exists between tau and iron accumulation in these diseases. The aims of this thesis were to understand, 1) how does tau participate in neurodegeneration; 2) whether tau is involved in brain iron homeostasis; and 3) whether this putative interaction contributes to neurodegeneration in the tauopathies. The normal function of tau has remained elusive, partly owing to the fact that tau knockout mice (tau KO) have been reported to be viable and fertile without behavioural deficits or neurodegeneration. These mice, however, have not extensively been investigated older than 7-months of age. Therefore, an analysis of aged (12-24 months) tau KO mice was undertaken in this thesis. Aged tau KO mice exhibited features of dementia (reduction of brain wet weight, neural cortical atrophy and cognitive impairment) and parkinsonism (L-DOPA responsive motor disability, neuron loss in substantia nigra [SN], striatal dopamine reduction and dopaminergic terminal atrophy). These observations may have implications for AD, which have been reported to exhibit reduced soluble tau in affected regions, and also PD, which was shown to have a similar reduction in this thesis. Iron accumulation was observed in the brains of aged tau KO mice. This specific brain-iron accumulation was prevented by chronic, orally administration of clioquinol, a moderate iron chelator previously reported to prevent MPTP-induced parkinsonism. When administration commenced before disease onset (6-months-of-age), chronic iron chelation prevented the onset of disease phenotype and neuronal loss in tau KO mice at advanced age. Likewise, treatment with clioquinol after the onset of disease (12-months-of-age) prevented further atrophy, and ameliorated behavioural disability. Therefore, tau depletion (as also observed in AD and PD) may engender pro−oxidant neuronal Fe2+ elevation preceding neurodegeneration. The mechanism of tau-induced iron accumulation was investigated in this thesis, which revealed a previously overlooked functional interaction between tau and the AD-implicated, amyloid precursor protein (APP). Immature APP undergoes several post-translational modifications before it is transported to the cell surface where it functions as an iron-export ferroxidase. Deletion of tau decreased the presence of mature APP presented on the cell surface which prevented the efficient neural export of iron. Disrupted trafficking of APP could therefore explain iron accumulation in the tau KO mouse, and in diseases exhibiting soluble tau reduction. Tau reduction may also be pharmacologically induced by the cation, lithium, which is a drug for bipolar disorder. In this thesis, lithium chloride caused intracellular iron accumulation and did not affect copper or zinc. This accumulation was abolished when treated to neurons that lacked tau or APP, demonstrating that lithium-induced iron accumulation was mediated by disruption to the tau-APP axis presented in this thesis. Lithium treatment has been previously associated with Parkinsonian side-effects; in this thesis, oral administration of lithium (in an upper-therapeutic range) to background mice caused brain-iron accumulation accompanying Parkinsonian neurodegeneration (motor disability, neuronal loss in SN, dopamine reduction in striatum). Given these striking findings, an MRI-analysis of iron in the brains of individuals who were treated with lithium (for three months) was performed, which revealed evidence of reversible iron elevation in selected regions upon treatment. This thesis, which investigated the function of tau and its loss-of-function phenotype, concluded that the reduction of soluble tau primes neurons for age-dependent neurodegeneration by decreasing APP-mediated iron export. Therefore, strategies that maintain tau solubility, or reduce iron content, may be promising therapeutic strategies for diseases featuring soluble tau loss such as AD and PD.