Year: 2020
Type: dissertation
Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder characterised by the progressive loss of dopaminergic neurons, particularly in the ventral substantia nigra. Growing evidence implicates biometal dyshomeostasis and subsequent metal-catalysed neurotoxicity in vulnerable regions of the PD brain. Through meta-analysis, I confirm previously reported reductions in Cu, and elevations in Fe specifically in the substantia nigra of the PD brain, which are not reflected by similar changes in biofluid tissues. These changes are further restricted to the soluble fraction of nigral tissue – suggesting that soluble metalloproteins may be affected by these biometal perturbations. Superoxide dismutase 1 (SOD1) is one soluble Cu-associated protein that has recently demonstrated impaired antioxidant capacity and altered structural conformation in the PD brain and may present with an altered metalation profile in PD brain. I describe, for the first time, the cutting-edge technique of simultaneous synchrotron X-ray fluorescence microscopy and ptychography performed in situ to identify and directly image Lewy bodies, SOD1 aggregates and neuromelanin in human PD substantia nigra. The resulting nanoscale imaging demonstrate that SOD1 and Lewy body proteinopathies share similar structures. SOD1 and Lewy aggregates also exhibited similar elemental compositions, suggesting that these distinct proteinaceous aggregates may share an overlapping protein misfolding pathway. Further, I demonstrate an altered Cu:Zn ratio in SOD1 aggregates, supporting the hypothesis that altered metalation of SOD1 results in aggregate formation in this Cu-deficient region. These data suggest that Cu dyshomeostasis in the vulnerable substantia nigra of the PD brain may be attenuated by biometal modulation therapies, and that SOD1 may present as a viable therapeutic target for PD.
Author: Sian Genoud
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3041713611