Genoud, S, Senior, AM, Hare, DJ & Double, KL 2020, 'Meta-analysis of copper and iron in Parkinson's disease brain and biofluids.', Movement disorders : official journal of the Movement Disorder Society.View/Download from: Publisher's site
BACKGROUND:Variations in study quality and design complicate interpretation of the clinical significance of consistently reported changes in copper and iron levels in human Parkinson's disease brain and biofluids. METHODS:We systematically searched literature databases for quantitative reports of biometal levels in the degenerating substantia nigra (SN), CSF, serum, and plasma in Parkinson's disease compared with healthy age-matched controls and assessed the quality of these publications. The primary outcomes of our analysis confirmed SN copper and iron levels are decreased and increased, respectively, in the Parkinson's disease brain. We applied a novel Quality Assessment Scale for Human Tissue to categorize the quality of individual studies and investigated the effects of study quality on our outcomes. We undertook a random-effects meta-analysis and meta-regression subgroup analysis. RESULTS:In the 18 eligible studies identified (211 Parkinson's disease, 215 control cases), SN copper levels were significantly lower (d, -2.00; 95% CI, -2.81 to -1.19; P < 0.001), and iron levels were significantly higher (d, 1.31; 95% CI, 0.38-2.24; P < 0.01) in Parkinson's disease. No changes were detected in CSF, serum, or plasma for any metals (29 studies; 2443 Parkinson's disease and 2183 control cases) except serum iron, which was lower in Parkinson's disease (14 studies; 1177 Parkinson's disease and 1447 control cases). CONCLUSIONS:Reductions in copper levels and elevations in iron were confirmed as characteristic of the degenerating SN of Parkinson's disease. Iron in serum was also changed, but in the opposite direction to that in the SN and to a lesser extent. © 2019 International Parkinson and Movement Disorder Society.
Genoud, S, Roberts, BR, Gunn, AP, Halliday, GM, Lewis, SJG, Ball, HJ, Hare, DJ & Double, KL 2017, 'Subcellular compartmentalisation of copper, iron, manganese, and zinc in the Parkinson's disease brain.', Metallomics: integrated biometal science, vol. 9, no. 10, pp. 1447-1455.View/Download from: Publisher's site
Elevated iron and decreased copper levels are cardinal features of the degenerating substantia nigra pars compacta in the Parkinson's disease brain. Both of these redox-active metals, and fellow transition metals manganese and zinc, are found at high concentrations within the midbrain and participate in a range of unique biological reactions. We examined the total metal content and cellular compartmentalisation of manganese, iron, copper and zinc in the degenerating substantia nigra, disease-affected but non-degenerating fusiform gyrus, and unaffected occipital cortex in the post mortem Parkinson's disease brain compared with age-matched controls. An expected increase in iron and a decrease in copper concentration was isolated to the soluble cellular fraction, encompassing both interstitial and cytosolic metals and metal-binding proteins, rather than the membrane-associated or insoluble fractions. Manganese and zinc levels did not differ between experimental groups. Altered Fe and Cu levels were unrelated to Braak pathological staging in our cases of late-stage (Braak stage V and VI) disease. The data supports our hypothesis that regional alterations in Fe and Cu, and in proteins that utilise these metals, contribute to the regional selectively of neuronal vulnerability in this disorder.
Trist, BG, Davies, KM, Cottam, V, Genoud, S, Ortega, R, Roudeau, S, Carmona, A, De Silva, K, Wasinger, V, Lewis, SJG, Sachdev, P, Smith, B, Troakes, C, Vance, C, Shaw, C, Al-Sarraj, S, Ball, HJ, Halliday, GM, Hare, DJ & Double, KL 2017, 'Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson's disease brain.', Acta Neuropathologica, vol. 134, no. 1, pp. 113-127.View/Download from: Publisher's site
Neuronal loss in numerous neurodegenerative disorders has been linked to protein aggregation and oxidative stress. Emerging data regarding overlapping proteinopathy in traditionally distinct neurodegenerative diseases suggest that disease-modifying treatments targeting these pathological features may exhibit efficacy across multiple disorders. Here, we describe proteinopathy distinct from classic synucleinopathy, predominantly comprised of the anti-oxidant enzyme superoxide dismutase-1 (SOD1), in the Parkinson's disease brain. Significant expression of this pathology closely reflected the regional pattern of neuronal loss. The protein composition and non-amyloid macrostructure of these novel aggregates closely resembles that of neurotoxic SOD1 deposits in SOD1-associated familial amyotrophic lateral sclerosis (fALS). Consistent with the hypothesis that deposition of protein aggregates in neurodegenerative disorders reflects upstream dysfunction, we demonstrated that SOD1 in the Parkinson's disease brain exhibits evidence of misfolding and metal deficiency, similar to that seen in mutant SOD1 in fALS. Our data suggest common mechanisms of toxic SOD1 aggregation in both disorders and a potential role for SOD1 dysfunction in neuronal loss in the Parkinson's disease brain. This shared restricted proteinopathy highlights the potential translation of therapeutic approaches targeting SOD1 toxicity, already in clinical trials for ALS, into disease-modifying treatments for Parkinson's disease.