“Science is a way of thinking much more than it is a body of knowledge.” Carl Sagan
“Imagination is more important than knowledge.” Albert Einstein
What is Manganese? Manganese is abbreviated by the symbol Mn and it is atomic number 25 (see Periodic Table of the Elements). Manganese is considered a transition metal, which is important for industrial alloys like stainless steel. In human biology, manganese is an essential nutrient, Manganese is found in nuts, legumes, seeds, tea, whole grains, and leafy green vegetables. We typically use manganese in metabolic pathways and it helps facilitate biochemical processing of proteins, carbohydrates, and cholesterol. Specifically, in the brain, manganese is a needed metabolic cofactor for several enzymes in neurons and glial cells, and in neurotransmitter assembly and processing. We require only trace amounts of manganese for its daily function. Although manganese is a valuable substance, excessive accumulation of manganese occurs in the basal ganglia region of the brain to cause a neurological defect very similar to Parkinson’s. Please Note: Manganese is not to be confused with Magnesium (symbol of Mg and atomic number 12, and Mg is an alkaline earth metal).
“Reality is that which, when you stop believing in it, doesn’t go away.” Philip K. Dick
Manganism: In 1837, John Couper described two Scottish workers who were grinding manganese, both workers had loss of motor activity but with no tremor. This neurotoxic dose of manganese in these workers came to be known as manganism. Since then, unfortunately, by occupational exposure to manganese (usually welders and miners), we have learned about manganism. We define manganism as a neurological disorder from increased exposure to manganese due to occupational settings and which is characterized by mood changes and a syndrome that resembles Parkinson’s.
The typical symptoms associated with manganism include the following changes:
• increased anxiety;
• loss of memory;
• loss of concentration;
• resting tumor;
• muscle and joint pain;
• dystonia of the trunk and extremities;
• extrapyramidal movement disorder that resembles Parkinson’s except with a characteristic “cock-walk” and it is difficult to walk backwards.
“If you thought that science was certain – well, that is just an error on your part.” Richard P. Feynman
Basal Ganglia Changes are Different Comparing Manganism and Parkinson’s: The basal ganglia will be reviewed in a future blog post. The basal ganglia affects the initiation and execution of voluntary movements (motor control), motor learning, executive function and related behavior, and emotions. From autopsy studies, it has been shown that different regions of the basal ganglia are affected in Manganism compared to Parkinson’s, as noted below:
• The highest level of manganese under normal conditions is found in the globus pallidus. Under conditions of occupational exposure of prolonged and excessive amounts of manganese, the primary neuropathological target of Manganism remains the globus pallidus (particularly the internal segment) [red box area]. Newer studies have noted the accumulation of manganese in the dopamine-rich regions of the basal ganglia. More specifically, basal ganglia mitochondria had substantial deposits of manganese.
• The primary neuropathological target of Parkinson‘s is the substantia nigra (particularly the pars compacta region) [purple box area] and the presence of Lewy bodies.
“The joy of discovery is certainly the liveliest that the mind of man can ever feel.” Claude Bernard
Common Links Between Manganism and Parkinson’s: In a laboratory setting, manganese increases the expression of a-synuclein, and then it promotes a-synuclein aggregation. An evolving scientific theme is the role of manganese to dysregulate a-synuclein’s function, which further links the clinical aspects of manganism to idiopathic Parkinson’s. Thus, both manganism and Parkinson’s lead to increased amounts of aggregated a-synuclein that negatively influence dopaminergic cells.
Both manganism and Parkinson’s result in mitochondria dysfunction that promotes neurotoxicity. The primary storage site for intracellular manganese is the mitochondria. However, excessive accumulation of intracellular manganese results in oxidative mitochondrial damage and oxidative stress. Combining mitochondrial dysfunction and aggregated a-synuclein potentially reveal a common mechanism between manganism and idiopathic Parkinson’s.
“All truths are easy to understand once they are discovered; the point is to discover them.” Galileo Galilei
In an interesting paper, recently published in Science Signaling (2019), Harischandra et al., further studied the mechanism of manganism. They studied how manganese promoted disease using both in vitro and in vivo models, and translational work with blood plasma samples obtained from welders.
Synucleopathies are disorders marked by the presence of Lewy bodies (which are cytoplasmic inclusions) that contain a-synuclein and ubiquitin. Found within this group of disorders includes Parkinson’s, Multiple System Atrophy (MSA), and diffuse Lewy Body Disease (LBD). While we still are unclear to the normal physiological function of a-synuclein, we do know that the presence of these inclusion bodies is toxic to the brain/central nervous system (CNS).
An emerging concept is the spread of these pathogenic mis-folded a-synuclein molecules throughout the CNS may consist of cell-to-cell transmission. Imagine a process where a prion-like process seeds (or spreads) these aggregates (mis-folded) a-synuclein molecules from neuron-to-neuron. The ultimate result is pathogenic (disease causing) because it activates the neuroinflammatory process (pro-inflammatory) and the response is neurodegeneration (neuron cell dysfunction/death).
Here is a brief overview of the results from the Harischandra et al. paper:
- A model system of a-synuclein (tagged for detection)-expressing neuronal cells, when exposed to manganese, upregulated oligomeric secretion of a-synuclein in exosomes. [Exosomes are nano-sized vesicle secreted from cells that contain various amounts of proteins and nucleic acids. Exosomes have a lipid bilayer membrane, and they are secreted out of the by exocytosis.]
- Adding purified manganese-induced neuronal cell exosomes to microglia cells promotes a neuroinflammatory response. The inflammatory process was shown by the release of pro-inflammatory cytokines from the microglia cells. These results are important because it shows that (i) exosomes are biologically active and (ii) capable of activating a pro-inflammatory response in microglial cells. [Microglial cells are a unique type of macrophage, a cell that can be both beneficial in a cell-regulatory role (immune function) and it can be detrimental because it can fuel the fire to neuroinflammation in the central nervous system (CNS).]
- The manganese-induced a-synuclein-containing exosomes were capable of causing neuronal cell death. The process of cell death was by apoptosis from the activation of microglia cell pro-inflammatory cytokines. [Apoptosis is a specialized process of cell death that follows a programmed sequence of events that leads to the destruction of cells.]
- Manganese induced cell-to-cell transmission of aggregated a-synuclein.
- Aggregated a-synuclein promotes neurotoxIcity that leads to motor dysfunction in mice, and the effect is enhanced by the addition of manganese.’
- Exposure of neuronal cells to manganese enables cell-to-cell transfer of a-synuclein aggregates, which results in neuronal cell dysfunction. Further mechanistic work revealed that the released a-synuclein was found in exosomes.
- Mice injected with a-synuclein-containing exosomes (produced by manganese-exposure to cells) showed a Parkinson’s-like motor deficient.
- Finally, blood samples from arc welders showed increased amounts of a-synuclein-containing exosomes when compared to aged-match people who were not welders. [Occupational exposure to large amounts of manganese leads to a Parkinson’s-like disorder named manganism.]
“The grand aim of all science is to cover the greatest number of empirical facts by logical deduction from the smallest number of hypotheses or axioms.” Albert Einstein
Conclusion: Mechanistic insight from one disorder (Manganism) to another further unites and clarifies other a-synuclein-based diseases like Parkinson’s. Advancing this kind of information allows one potentially to develop probes for early detection of Parkinson’s. Furthermore, this type of study could allow for a better understanding of the pathogenic process of Parkinson’s, which could enable researchers to develop novel therapies.
“Nothing in life is certain except death, taxes and the second law of thermodynamics. All three are processes in which useful or accessible forms of some quantity, such as energy or money, are transformed into useless, inaccessible forms of the same quantity. That is not to say that these three processes don’t have fringe benefits: taxes pay for roads and schools; the second law of thermodynamics drives cars, computers and metabolism; and death, at the very least, opens up tenured faculty positions.” Seth Lloyd
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Harischandra DS, Ghaisas S, Rokad D, Zamanian M, Jin H, Anantharam V, Kimber M, Kanthasamy A, Kanthasamy AG. Environmental neurotoxicant manganese regulates exosome-mediated extracellular miRNAs in cell culture model of Parkinson’s disease: Relevance to α-synuclein misfolding in metal neurotoxicity. Neurotoxicology. 2018;64:267-77.
Sarkar S, Malovic E, Harischandra DS, Ngwa HA, Ghosh A, Hogan C, Rokad D, Zenitsky G, Jin H, Anantharam V. Manganese exposure induces neuroinflammation by impairing mitochondrial dynamics in astrocytes. Neurotoxicology. 2018;64:204-18.
Harischandra DS, Rokad D, Neal ML, Ghaisas S, Manne S, Sarkar S, Panicker N, Zenitsky G, Jin H, Lewis M, Huang X, Anantharam V, Kanthasamy A, Kanthasamy AG. Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein. Science Signaling. 2019;12(572):eaau4543. doi: 10.1126/scisignal.aau4543.
Cover Photo Credit: https://images.app.goo.gl/jhSEjKzj1P5Hvequ5