Ke T et al. (2019) Neurochem Res "Role of Astrocytes in Manganese Neurotoxicity Revisited."

Rizor A, Lee E, Ke T, Sidoryk-Wegrzynowicz M, Pajarillo E, Aschner M, Soares FAA

[Neurochem Res, 2019]

Manganese (Mn) overexposure is a public health concern due to its widespread industrial usage and the risk for environmental contamination. The clinical symptoms of Mn neurotoxicity, or manganism, share several pathological features of Parkinson's disease (PD). Biologically, Mn is an essential trace element, and Mn in the brain is preferentially localized in astrocytes. This review summarizes the role of astrocytes in Mn-induced neurotoxicity, specifically on the role of neurotransmitter recycling, neuroinflammation, and genetics. Mn overexposure can dysregulate astrocytic cycling of glutamine (Gln) and glutamate (Glu), which is the basis for Mn-induced excitotoxic neuronal injury. In addition, reactive astrocytes are important mediators of Mn-induced neuronal damage by potentiating neuroinflammation. Genetic studies, including those with Caenorhabditis elegans (C. elegans) have uncovered several genes associated with Mn neurotoxicity. Though we have yet to fully understand the role of astrocytes in the pathologic changes characteristic of manganism, significant strides have been made over the last two decades in deciphering the role of astrocytes in Mn-induced neurotoxicity and neurodegeneration.

Peres TV et al. (2016) BMC Pharmacol Toxicol ""Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies"."

Peres TV, Schettinger MR, Aschner M, Carvalho F, Bowman AB, Chen P, Avila DS

[BMC Pharmacol Toxicol, 2016]

Manganese (Mn) is an essential heavy metal. However, Mn's nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson's disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.

Taghert PH et al. (2012) Neuron "Peptide neuromodulation in invertebrate model systems."

Nitabach MN, Taghert PH

[Neuron, 2012]

Neuropeptides modulate neural circuits controlling adaptive animal behaviors and physiological processes, such as feeding/metabolism, reproductive behaviors, circadian rhythms, central pattern generation, and sensorimotor integration. Invertebrate model systems have enabled detailed experimental analysis using combined genetic, behavioral, and physiological approaches. Here we review selected examples of neuropeptide modulation in crustaceans, mollusks, insects, and nematodes, with a particular emphasis on the genetic model organisms Drosophila melanogaster and Caenorhabditis elegans, where remarkable progress has been made. On the basis of this survey, we provide several integrating conceptual principles for understanding how neuropeptides modulate circuit function, and also propose that continued progress in this area requires increased emphasis on the development of richer, more sophisticated behavioral paradigms.

Chakraborty S et al. (2012) J Trace Elem Med Biol "Altered manganese homeostasis: implications for BLI-3-dependent dopaminergic neurodegeneration and SKN-1 protection in C. elegans."

Chakraborty S, Aschner M

[J Trace Elem Med Biol, 2012]

The role of environmental factors in the etiology of neurodegenerative disorders, such as in Parkinson's disease (PD), has become increasingly imperative for examination, as genetics can only partially account for most cases. The heavy metal manganese (Mn) falls into this category of environmental contributors, as it is both essential but also neurotoxic upon overexposure and produces Parkinsonian symptomatology. In order to understand its toxicity, this review focuses on the various aspects of improper Mn homeostasis and its consequences using the genetically amenable Caenorhabditis elegans model. Namely, the roles of Mn transporter homologs for the divalent metal transporter 1 (DMT1) will be discussed, as Mn homeostasis is initially governed by proper cellular transport. Mn dyshomeostasis can result in enhanced oxidative stress through synergistic actions of dopamine oxidation that is dependent on the C. elegans dual oxidase BLI-3. Finally, neuroprotection conferred by the antioxidant transcription factor Nrf2 (C. elegans SKN-1) may signify a potential therapeutic approach against Mn toxicity.

Soares ATG et al. (2020) J Trace Elem Med Biol "The impact of manganese on neurotransmitter systems."

Khan H, Santamaria A, Tinkov AA, Soares ATG, Bowman AB, Skalny AV, Skalnaya MG, Avila DS, Silva AC, Tsatsakis A, Aschner M

[J Trace Elem Med Biol, 2020]

BACKGROUND: Manganese (Mn) is a metal ubiquitously present in nature and essential for many living organisms. As a trace element, it is required in small amounts for the proper functioning of several important enzymes, and reports of Mn deficiency are indeed rare. METHODS: This mini-review will cover aspects of Mn toxicokinetics and its impact on brain neurotransmission, as well as its Janus-faced effects on humans and other animal's health. RESULTS: The estimated safe upper limit of intracellular Mn for physiological function is in anarrow range of 20-53M.Therefore, intake of higher levels of Mn and the outcomes, especially to the nervous system, have been well documented. CONCLUSION: The metal affects mostly the brain by accumulating in specific areas, altering cognitive functions and locomotion, thus severely impacting the health of the exposed organisms.

Au C et al. (2008) Neurotoxicology "Manganese transport in eukaryotes: the role of DMT1."

Au C, Benedetto A, Aschner M

[Neurotoxicology, 2008]

Manganese (Mn) is a transition metal that is essential for normal cell growth and development, but is toxic at high concentrations. While Mn deficiency is uncommon in humans, Mn toxicity is known to be readily prevalent due to occupational overexposure in miners, smelters and possibly welders. Excessive exposure to Mn can cause Parkinson''s disease-like syndrome; patients typically exhibit extrapyramidal symptoms that include tremor, rigidity and hypokinesia [Calne DB, Chu NS, Huang CC, Lu CS, Olanow W. Manganism and idiopathic parkinsonism: similarities and differences. Neurology 1994;44(9):1583-6; Dobson AW, Erikson KM, Aschner M. Manganese neurotoxicity. Ann NY Acad Sci 2004;1012:115-28]. Mn-induced motor neuron diseases have been the subjects of numerous studies; however, this review is not intended to discuss its neurotoxic potential or its role in the etiology of motor neuron disorders. Rather, it will focus on Mn uptake and transport via the orthologues of the divalent metal transporter (DMT1) and its possible implications to Mn toxicity in various categories of eukaryotic systems, such as in vitro cell lines, in vivo rodents, the fruitfly, Drosophila melanogaster, the honeybee, Apis mellifera L., the nematode, Caenorhabditis elegans and the baker''s yeast, Saccharomyces cerevisiae.

Ghosh DD et al. (2017) Curr Opin Neurobiol "Multisensory integration in C. elegans."

Ghosh DD, Harris G, Nitabach MN, Zhang Y

[Curr Opin Neurobiol, 2017]

Multisensory integration is a neural process by which signals from two or more distinct sensory channels are simultaneously processed to form a more coherent representation of the environment. Multisensory integration, especially when combined with a survey of internal states, provides selective advantages for animals navigating complex environments. Despite appreciation of the importance of multisensory integration in behavior, the underlying molecular and cellular mechanisms remain poorly understood. Recent work looking at how Caenorhabditis elegans makes multisensory decisions has yielded mechanistic insights into how a relatively simple and well-defined nervous system employs circuit motifs of defined features, synaptic signals and extrasynaptic neurotransmission, as well as neuromodulators in processing and integrating multiple sensory inputs to generate flexible and adaptive behavioral outputs.

Kunst M et al. (2014) Crit Rev Biochem Mol Biol "Rhythmic control of activity and sleep by class B1 GPCRs."

Ghosh DD, Tso MC, Kunst M, Nitabach MN, Herzog ED

[Crit Rev Biochem Mol Biol, 2014]

Members of the class B1 family of G-protein coupled receptors (GPCRs) whose ligands are neuropeptides have been implicated in regulation of circadian rhythms and sleep in diverse metazoan clades. This review discusses the cellular and molecular mechanisms by which class B1 GPCRs, especially the mammalian VPAC2 receptor and its functional homologue PDFR in Drosophila and C. elegans, regulate arousal and daily rhythms of sleep and wake. There are remarkable parallels in the cellular and molecular roles played by class B1 intercellular signaling pathways in coordinating arousal and circadian timekeeping across multiple cells and tissues in these very different genetic model organisms.

Martins AC et al. (2022) Biomolecules "Caenorhabditis elegans as a Model to Study Manganese-Induced Neurotoxicity."

Bornhorst J, Aschner M, Nicolai MM, Martins AC, Ke T, Li J, Moura AV, Gubert P, Bowman AB

[Biomolecules, 2022]

Caenorhabditis elegans (C. elegans) is a nematode present worldwide. The worm shows homology to mammalian systems and expresses approximately 40% of human disease-related genes. Since Dr. Sydney Brenner first proposed C. elegans as an advantageous experimental worm-model system for genetic approaches, increasing numbers of studies using C. elegans as a tool to investigate topics in several fields of biochemistry, neuroscience, pharmacology, and toxicology have been performed. In this regard, C. elegans has been used to characterize the molecular mechanisms and affected pathways caused by metals that lead to neurotoxicity, as well as the pathophysiological interrelationship between metal exposure and ongoing neurodegenerative disorders. Several toxic metals, such as lead, cadmium, and mercury, are recognized as important environmental contaminants, and their exposure is associated with toxic effects on the human body. Essential elements that are required to maintain cellular homeostasis and normal physiological functions may also be toxic when accumulated at higher concentrations. For instance, manganese (Mn) is a trace essential element that participates in numerous biological processes, such as enzymatic activities, energy metabolism, and maintenance of cell functions. However, Mn overexposure is associated with behavioral changes in C. elegans, which are consistent with the dopaminergic system being the primary target of Mn neurotoxicity. Caenorhabditis elegans has been shown to be an important tool that allows for studies on neuron morphology using fluorescent transgenic worms. Moreover, behavioral tests may be conducted using worms, and neurotransmitter determination and related gene expression are likely to change after Mn exposure. Likewise, mutant worms may be used to study molecular mechanisms in Mn toxicity, as well as the expression of proteins responsible for the biosynthesis, transport, storage, and uptake of dopamine. Furthermore, this review highlights some advantages and limitations of using the experimental model of C. elegans and provides guidance for potential future applications of this model in studies directed toward assessing for Mn neurotoxicity and related mechanisms.

Nikoletopoulou V et al. (2017) Neurosci Lett "The PMR1 pump in alpha-synuclein toxicity and neurodegeneration."

Tavernarakis N, Nikoletopoulou V

[Neurosci Lett, 2017]

Proteinopathies constitute a diverse group of devastating neurodegenerative disorders, characterized by aberrant aggregation of specific proteins within neurons and in the brain parenchyma. Parkinson's disease (PD) is among the most common proteinopathies, caused by the accumulation of different species of -synuclein and the formation of protein inclusions known as Lewy bodies. Although several mutations in the -synuclein gene have been linked to PD, the mechanisms mediating the aggregation and toxicity of -synuclein are not fully understood. Here, we review recent evidence that highlight an intricate interplay between -synuclein and ionostasis, focusing on the PMR1 pump, a Golgi resident Ca(2+)/Mn(2+) P-type ATPase, which plays a pivotal role in regulating the intracellular levels of calcium and manganese ions.