Florey Department of Neuroscience and Mental Health - Theses

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Subject: neurodegeneration × Author: Ramirez Munoz, Alejandra Elvira ×

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    The role of copper in neurodegenerative ubiquitinopathy
    Ramirez Munoz, Alejandra Elvira ( 2019)
    Ubiquitin (Ub) is one of the most stable and soluble intracellular proteins. Intriguingly, the accumulation of intracellular Ub is associated to protein aggregates that are characteristic features of neurodegenerative diseases. Nevertheless, the factors that promote Ub aggregation and/or accumulation are unknown. Conversely, in vitro studies have shown that the interaction between Ub and cupric copper (Cu(II)) promotes the formation of high molecular weight (HMW), SDS and trypsin resistant, named as Ubres species. There is a general consensus that bioavailable copper only exists as Cu(I) in the cytosol, and there is limited evidence to support the presence of Cu(II) in this compartment. However, in vivo Ub denaturation may require a pool of labile Cu(II) that, to date, has not been identified. Cu(I) is maintained in the cytosol by a complex network of copper ligands and chaperones, and by reducing agents, predominantly glutathione (GSH). Brain glutathione depletion as well as copper dyshomeostasis are features of neurodegeneration. Therefore, we hypothesized that intracellular Cu(II) is elevated by the loss of GSH in these diseases. In this thesis, using XANES and a fluorescent Cu(II)-probe (CBS), we demonstrated that labile Cu(II) pools are present in the cytosol. Moreover, our results showed that decreasing GSH levels in cells, increases intracellular Cu(II) levels. Loss of Cu(I) and the emergence of Cu(II) may exacerbate the metabolic brain lesions in these neurodegenerative disorders. In fact, the increase in intracellular Cu(II) concurred with an increase in the levels of HMW Ub species in a SDS-insoluble cellular fraction, which were resistant to enzymatic proteolysis, characteristic features of Ubres species. We also found the presence of these Ubres species in brain tissue from Alzheimer’s disease and Lewy body dementia diagnosed patients. The outcomes of this research shed lights on the mechanism that may explain the ubiquinopathy of these neurogenerative disorders and may help to develop novel therapeutic strategies for these diseases.