Association of metals with the risk and clinical characteristics of Parkinson's disease
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disease and has increased in prevalence in developed countries. The main pathological features of PD are progressive dopaminergic neuronal loss in the pars compacta of the substantia nigra (SNpc) and deposition of intracellular Lewy bodies.
Metals have been implicated in PD pathophysiology. Iron is the most extensively studied metal in the PD brain, and its elevation in SN of PD patients has been consistently reported [1]. The ferroxidase activity of ceruloplasmin that facilitates iron export from cells, was reduced in SN of PD brain, a probable mechanism for iron accumulation in the same region [2]. Iron accumulation in SNpc causes oxidative stress-induced damage to dopaminergic neurons, in turn leading to Parkinsonism [3]. Copper acts as a cofactor in many key enzymes, including cytochrome c oxidase, copper/zinc superoxide dismutase, dopamine β-hydroxylase, and ceruloplasmin, which are crucial for neurological development and function [4]. Reduced copper in SNpc accompanies elevated nigral iron [2]. Such alterations of iron and copper levels could promote toxic redox cycling by catalyzing the formation of reactive oxygen species [5]. In addition, both metals interact with the pathogenic α-synuclein (αSyn) protein to inhibit formation of αSyn filaments with concomitant accumulation of toxic αSyn oligomers [6]. Zinc is present within synaptic vesicles and has a prime role in synaptic transmission by serving as an endogenous neuromodulator. Zinc, as a constituent of copper/zinc superoxide dismutase, helps to protect cells from superoxide radical damage [7]. Recent studies have showed that PARK9/ATP13A2, one of the causative genes for familial PD, regulates cellular level of zinc and promotes αSyn externalization via exosomes, and its deficiency causes zinc dyshomeostasis and mitochondrial dysfunction [8,9].
Previous studies have demonstrated changes in levels of metals in blood, urine, and the cerebrospinal fluid (CSF) in PD patients, but the results have been inconsistent among the studies [[10], [11], [12]]. Moreover, the contribution of metals for specific clinical or symptomatic characteristics of PD patients remains to be elucidated. Thus, this population study investigated the associations of serum metals (iron, copper, and zinc) with PD risk and specific clinical characteristics of PD patients, including sex-related differences.
Section snippets
Study subjects
The institutional review board of Asan Medical Center (Seoul, Korea) approved this study, and all subjects provided informed consent in accordance with the institutional review board regulations. The study subjects consisted of 325 patients with PD (175 men and 150 women) and 304 controls (141 men and 163 women), who were recruited through the movement disorders clinic at Asan Medical Center and differentiated on the basis of the clinical diagnosis criteria of the United Kingdom Parkinson's
Results
The demographic and clinical characteristics of PD patients and controls are summarized in Table 1. There were no significant differences in age and sex between the PD patients and controls. MMSE scores were significantly lower in the PD patients than in the controls.
Discussion
In this study, we found that serum metal levels were associated with PD risk and specific clinical features of PD. The associations of metals with some clinical features of PD were dependent on the sex of the PD patients. In particular, the most interesting finding is that the level of copper was strongly correlated with PD risk or specific clinical features among the metal elements analyzed. Higher serum copper levels were associated with decreased PD risk. In women with PD, higher serum
Conclusion
This study firstly found significant associations between serum metals and PD risk or essential clinical features of PD. Above all, copper levels in serum were strongly associated with the risk or incidence of PD-related clinical features or dementia, allowing evaluation of the influence of the metal on PD pathogenesis.
Authors' contributions
MJK, AIB, J-YL, and SJC conceived, designed and organized the study. MJK, S-BO, JK, KK, H-SR, MSK, SA, J-YL, and SJC performed the experiments and the data analysis. MJK, SA, AIB, J-YL, and SJC wrote the manuscript. All authors reviewed and approved the final draft of the manuscript.
Disclosures
All authors have no conflict of interest to declare, but Dr. Bush AI is a shareholder in Prana Biotechnology Ltd, Cogstate Ltd, Mesoblast Ltd, NextVet Ltd, Brighton Biotech LLC and Cogstate Ltd, and a consultant for Collaborative Medicinal Development Pty Ltd.
Acknowledgement and funding
This study was supported by a grant of the Korea Healthcare Technology R & D Project, Ministry of Health & Welfare, Republic of Korea (HI17C0328) and a grant (2013-0416) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.
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2022, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopyCitation Excerpt :Maintaining a healthy balance of copper ions, which are the key structural components of many proteins, is important for various physiological and pathological processes [1]. Many serious neurodegenerative, genetic, and metabolic diseases, such as liver and kidney damage [2], neurotoxicity [3], Parkinson’s disease [4], Alzheimer’s disease [5], Wilson’s disease [6], Menkes disease [7], obesity, and diabetes [8], have been associated with the misregulation of copper in the body. Furthermore, excess copper waste produced by the mining and smelting industries is a significant cause of environmental pollution [9].
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2020, Ageing Research ReviewsCitation Excerpt :CSF copper was largely reported to be unchanged (Ahmed and Santosh, 2010; Alimonti et al., 2007; Bocca et al., 2006; Karpenko et al., 2018) although there were two reports of increases (Boll et al., 2008; Pall et al., 1987) and one of decreases (Sanyal et al., 2016). Investigations of copper in the blood were conflicting, with four reports of increases (Bocca et al., 2006; Fukushima et al., 2013; Hegde et al., 2004; Kumudini et al., 2014), six of decreases (Bharucha et al., 2008; Bocca et al., 2006; Kim et al., 2018; Sanyal et al., 2016; Younes-Mhenni et al., 2013; Zhao et al., 2013) and one finding of no change (Ling and Bhidayasiri, 2011). As such, biofluid findings aren’t conclusive enough to suggest viability of blood copper as a biomarker in PD.