Florey Department of Neuroscience and Mental Health - Theses
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Itemα-synuclein, iron and Multiple System Atrophy( 2019)Multiple System Atrophy (MSA) is an atypical parkinsonian disorder characterised by progressive neurodegeneration in substantia nigra, striatum, cerebellum, pons, inferior olives and spinal cord. The presence of protein aggregates primarily composed of misfolded α-synuclein in oligodendrocytes is the pathological hallmark of MSA, classifying it as a synucleinopathy. However, the aetiology of MSA remains poorly understood and due to the lack of identification of potential targets for drug therapy, no disease modifying therapies are available. Brain region-specific changes in the metabolism of biological trace metals – especially iron and copper – have been reported in α-synucleinopathies like Parkinson’s disease but, their contribution in MSA pathogenesis requires further investigation. Hence, in this thesis, I studied the role of iron and copper in the pathogenesis of MSA using post mortem human MSA brains and a mouse model of MSA. Quantification of metal levels using inductively coupled plasma-mass spectrometry (ICP-MS) revealed an increase in cytosolic iron content in putamen and occipital cortex from MSA brains. Since ferritin is a major iron storage protein, the amount of iron bound to ferritin was investigated using size exclusion chromatography-ICP-MS and it was found that ferritin-bound iron remained unchanged in MSA brain. Furthermore, ferritin protein levels were also unchanged in MSA putamen and occipital cortex. In order to better understand how iron and copper levels change through the course of disease progression in MSA, I used a transgenic mouse model of MSA and studied age-dependent changes in these metals. I found increased iron in substantia nigra, putamen and cerebellum in aged MSA mice compared with non-transgenic littermates, and a copper-binding protein with a molecular weight consistent with ceruloplasmin had a significantly decreased copper content. Ceruloplasmin is a copper-dependent protein that is involved in iron export from cells. In addition, the levels of ferritin were found to be decreased. These results indicate that elevated iron in MSA mice may result from ceruloplasmin dysfunction. Decreased copper binding to ceruloplasmin may result into loss of activity and hence, impaired iron export from the cell leading to iron accumulation that could contribute to the ongoing neurodegeneration in MSA. I further investigated if administration of ceruloplasmin or deferiprone alleviated neuronal pathology and motor impairment in MSA mice. Deferiprone is a clinically approved iron chelator and exogenous ceruloplasmin administration has been shown to be therapeutic in animal models. Compared to vehicle treated mice, deferiprone and ceruloplasmin treatments prevented the decline in motor performance, prevented loss of substantia nigra neurons and reduced the number of α-synuclein aggregates in substantia nigra. The results from this proof of concept pre-clinical trial provide evidence that targeting iron in MSA could be a viable therapeutic option.