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Regulation of Trace Metals in Neurodegenerative and Neurodevelopmental Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 13211

Special Issue Editors

Dipartimento di Scienze di Laboratorio, Sezione Ricerca e Sviluppo, Ospedale Fatebenefratelli Isola Tiberina–Gemelli Isola, Via di Ponte Quattro Capi 39, 00186 Roma, Italy
Interests: neurodegenerative disorders; cancer; essential metals; Alzheimer’s disease; psychiatric disorders; copper; iron; zinc
Special Issues, Collections and Topics in MDPI journals
Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Kalyani 741245, West Bengal, India
Interests: Metals; ATOX1; ATP7B; Wilson disease; Alzheimer’s disease; copper; iron; zinc

Special Issue Information

Neurodegenerative dementias are a leading cause of death worldwide. Major neurodegenerative dementias are multifactorial disorders that share key pathophysiological processes. Recent advances in biology and medicine have introduced metals—particularly copper, iron, and zinc—as influencing agents in Alzheimer’s disease (AD), the most common form of dementia in the elderly. Increasing information has led to the development of new models or tools to characterize defective pathways of metal trafficking linked to neurodegenerative processes in AD and the rationale for phase II trials. In the same line, childhood/adulthood neurodevelopmental disorders are a global health concern, and metals could play a role as potential biomarkers for the differential diagnosis and as predictors of treatment response. We invite investigators to contribute original research and review articles that will stimulate the continuing efforts to understand the molecular pathology underlying metals in neurodegenerative and neurodevelopmental disorders. Potential topics include, but are not limited to:

  • Advances in metal toxicity and genetics;
  • Metals–proteins interplay and metals’ potential as biomarkers of subtypes or prognosis;
  • Role of inflammation related to trace metals;
  • Recent advances in drug strategy based on metallo-biology;
  • Mechanisms whereby aging increases susceptibility to trace elements toxicity/deficiency in the brain;
  • System biology/bioinformatics-based approaches.

Dr. Rosanna Squitti
Dr. Amit Pal
Guest Editors

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Keywords

  • alzheimer’s disease
  • neurodevelopmental disorders
  • metal
  • biomarker
  • copper
  • iron
  • zinc
  • oxidative stress

Published Papers (5 papers)

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Research

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27 pages, 2573 KiB  
Article
Novel Anti-Neuroinflammatory Properties of a Thiosemicarbazone–Pyridylhydrazone Copper(II) Complex
by Xin Yi Choo, Lachlan E. McInnes, Alexandra Grubman, Joanna M. Wasielewska, Irina Belaya, Emma Burrows, Hazel Quek, Jorge Cañas Martín, Sanna Loppi, Annika Sorvari, Dzhessi Rait, Andrew Powell, Clare Duncan, Jeffrey R. Liddell, Heikki Tanila, Jose M. Polo, Tarja Malm, Katja M. Kanninen, Paul S. Donnelly and Anthony R. White
Int. J. Mol. Sci. 2022, 23(18), 10722; https://doi.org/10.3390/ijms231810722 - 14 Sep 2022
Cited by 4 | Viewed by 2792
Abstract
Neuroinflammation has a major role in several brain disorders including Alzheimer’s disease (AD), yet at present there are no effective anti-neuroinflammatory therapeutics available. Copper(II) complexes of bis(thiosemicarbazones) (CuII(gtsm) and CuII(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, [...] Read more.
Neuroinflammation has a major role in several brain disorders including Alzheimer’s disease (AD), yet at present there are no effective anti-neuroinflammatory therapeutics available. Copper(II) complexes of bis(thiosemicarbazones) (CuII(gtsm) and CuII(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, with CuII(atsm) demonstrating beneficial outcomes on neuroinflammatory markers in vitro and in vivo. These findings suggest that copper(II) complexes could be harnessed as a new approach to modulate immune function in neurodegenerative diseases. In this study, we examined the anti-neuroinflammatory action of several low-molecular-weight, charge-neutral and lipophilic copper(II) complexes. Our analysis revealed that one compound, a thiosemicarbazone–pyridylhydrazone copper(II) complex (CuL5), delivered copper into cells in vitro and increased the concentration of copper in the brain in vivo. In a primary murine microglia culture, CuL5 was shown to decrease secretion of pro-inflammatory cytokine macrophage chemoattractant protein 1 (MCP-1) and expression of tumor necrosis factor alpha (Tnf), increase expression of metallothionein (Mt1), and modulate expression of Alzheimer’s disease-associated risk genes, Trem2 and Cd33. CuL5 also improved the phagocytic function of microglia in vitro. In 5xFAD model AD mice, treatment with CuL5 led to an improved performance in a spatial working memory test, while, interestingly, increased accumulation of amyloid plaques in treated mice. These findings demonstrate that CuL5 can induce anti-neuroinflammatory effects in vitro and provide selective benefit in vivo. The outcomes provide further support for the development of copper-based compounds to modulate neuroinflammation in brain diseases. Full article
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13 pages, 2479 KiB  
Article
Mn(II) Quinoline Complex (4QMn) Restores Proteostasis and Reduces Toxicity in Experimental Models of Huntington’s Disease
by Marián Merino, María Dolores Sequedo, Ana Virginia Sánchez-Sánchez, Mª Paz Clares, Enrique García-España, Rafael P. Vázquez-Manrique and José L. Mullor
Int. J. Mol. Sci. 2022, 23(16), 8936; https://doi.org/10.3390/ijms23168936 - 11 Aug 2022
Cited by 3 | Viewed by 1489
Abstract
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder, of the so-called minority diseases, due to its low prevalence. It is caused by an abnormally long track of glutamines (polyQs) in mutant huntingtin (mHtt), which makes the protein toxic and prone to aggregation. [...] Read more.
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder, of the so-called minority diseases, due to its low prevalence. It is caused by an abnormally long track of glutamines (polyQs) in mutant huntingtin (mHtt), which makes the protein toxic and prone to aggregation. Many pathways of clearance of badly-folded proteins are disrupted in neurons of patients with HD. In this work, we show that one Mn(II) quinone complex (4QMn), designed to work as an artificial superoxide dismutase, is able to activate both the ubiquitin-proteasome system and the autophagy pathway in vitro and in vivo models of HD. Activation of these pathways degrades mHtt and other protein-containing polyQs, which restores proteostasis in these models. Hence, we propose 4QMn as a potential drug to develop a therapy to treat HD. Full article
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Review

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16 pages, 1182 KiB  
Review
The Role of Zinc in the Treatment of Wilson’s Disease
by Abolfazl Avan, Anna Członkowska, Susan Gaskin, Alberto Granzotto, Stefano L. Sensi and Tjaard U. Hoogenraad
Int. J. Mol. Sci. 2022, 23(16), 9316; https://doi.org/10.3390/ijms23169316 - 18 Aug 2022
Cited by 12 | Viewed by 3107
Abstract
Wilson’s disease (WD) is a hereditary disorder of copper metabolism, producing abnormally high levels of non-ceruloplasmin-bound copper, the determinant of the pathogenic process causing brain and hepatic damage and dysfunction. Although the disease is invariably fatal without medication, it is treatable and many [...] Read more.
Wilson’s disease (WD) is a hereditary disorder of copper metabolism, producing abnormally high levels of non-ceruloplasmin-bound copper, the determinant of the pathogenic process causing brain and hepatic damage and dysfunction. Although the disease is invariably fatal without medication, it is treatable and many of its adverse effects are reversible. Diagnosis is difficult due to the large range and severity of symptoms. A high index of suspicion is required as patients may have only a few of the many possible biomarkers. The genetic prevalence of ATP7B variants indicates higher rates in the population than are currently diagnosed. Treatments have evolved from chelators that reduce stored copper to zinc, which reduces the toxic levels of circulating non-ceruloplasmin-bound copper. Zinc induces intestinal metallothionein, which blocks copper absorption and increases excretion in the stools, resulting in an improvement in symptoms. Two meta-analyses and several large retrospective studies indicate that zinc is equally effective as chelators for the treatment of WD, with the advantages of a very low level of toxicity and only the minor side effect of gastric disturbance. Zinc is recommended as a first-line treatment for neurological presentations and is gaining acceptance for hepatic presentations. It is universally recommended for lifelong maintenance therapy and for presymptomatic WD. Full article
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18 pages, 1277 KiB  
Review
Is There a Connection between the Metabolism of Copper, Sulfur, and Molybdenum in Alzheimer’s Disease? New Insights on Disease Etiology
by Fábio Cunha Coelho, Giselle Cerchiaro, Sheila Espírito Santo Araújo, João Paulo Lima Daher, Silvia Almeida Cardoso, Gustavo Fialho Coelho and Arthur Giraldi Guimarães
Int. J. Mol. Sci. 2022, 23(14), 7935; https://doi.org/10.3390/ijms23147935 - 19 Jul 2022
Cited by 5 | Viewed by 2450
Abstract
Alzheimer’s disease (AD) and other forms of dementia was ranked 3rd in both the Americas and Europe in 2019 in a World Health Organization (WHO) publication listing the leading causes of death and disability worldwide. Copper (Cu) imbalance has been reported in AD [...] Read more.
Alzheimer’s disease (AD) and other forms of dementia was ranked 3rd in both the Americas and Europe in 2019 in a World Health Organization (WHO) publication listing the leading causes of death and disability worldwide. Copper (Cu) imbalance has been reported in AD and increasing evidence suggests metal imbalance, including molybdenum (Mo), as a potential link with AD occurrence.We conducted an extensive literature review of the last 60 years of research on AD and its relationship with Cu, sulfur (S), and Mo at out of range levels.Weanalyzed the interactions among metallic elements’ metabolisms;Cu and Mo are biological antagonists, Mo is a sulfite oxidase and xanthine oxidase co-factor, and their low activities impair S metabolism and reduce uric acid, respectively. We found significant evidence in the literature of a new potential mechanism linking Cu imbalance to Mo and S abnormalities in AD etiology: under certain circumstances, the accumulation of Cu not bound to ceruloplasmin might affect the transport of Mo outside the blood vessels, causing a mild Mo deficiency that might lowerthe activity of Mo and S enzymes essential for neuronal activity. The current review provides an updated discussion of the plausible mechanisms combining Cu, S, and Mo alterations in AD. Full article
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20 pages, 1373 KiB  
Review
Regulatory miRNAs in Cardiovascular and Alzheimer’s Disease: A Focus on Copper
by Anna Sacco, Fabio Martelli, Amit Pal, Claudia Saraceno, Luisa Benussi, Roberta Ghidoni, Mauro Rongioletti and Rosanna Squitti
Int. J. Mol. Sci. 2022, 23(6), 3327; https://doi.org/10.3390/ijms23063327 - 19 Mar 2022
Cited by 3 | Viewed by 2620
Abstract
Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), are key regulators of differentiation and development. In the cell, transcription factors regulate the production of miRNA in response to different external stimuli. Copper (Cu) is a heavy metal and an essential micronutrient with widespread industrial applications. [...] Read more.
Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), are key regulators of differentiation and development. In the cell, transcription factors regulate the production of miRNA in response to different external stimuli. Copper (Cu) is a heavy metal and an essential micronutrient with widespread industrial applications. It is involved in a number of vital biological processes encompassing respiration, blood cell line maturation, and immune responses. In recent years, the link between deregulation of miRNAs’ functionality and the development of various pathologies as well as cardiovascular diseases (CVDs) has been extensively studied. Alzheimer’s disease (AD) is the most common cause of dementia in the elderly with a complex disease etiology, and its link with Cu abnormalities is being increasingly studied. A direct interaction between COMMD1, a regulator of the Cu pathway, and hypoxia-inducible factor (HIF) HIF-1a does exist in ischemic injury, but little information has been collected on the role of Cu in hypoxia associated with AD thus far. The current review deals with this matter in an attempt to structurally discuss the link between miRNA expression and Cu dysregulation in AD and CVDs. Full article
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