Ions in the Neurodegenerative Diseases (Part Two)
Part one of Ions in the Neurodegenerative Diseases discussed about the magnetite in the brain because of air pollution, aluminum, and ion channels in multiple sclerosis (MS). We can not overrule the ions in our body especially brain as ions are needed for electrical impulses across the membranes.
Parkinson's Disease (PD) and Lewy Bodies Dementia (LBD)
Membranes, including endosomes and lysosome, also relied on ion channels to communicate. A reduction in function of an ion channel in cellular organelles called lysosomes, also known as cells' waste removal and recycling centers may increase the risk of PD1. This disease is associated with the dysfunction of potassium (K+) channels2. In PD, aggregation of a small lipid-binding protein α-synuclein to Lewy bodies, are detected primarily in dopaminergic (DA) neurons in a brain region called the substantia nigra pars compacta (SNc). There are roles of heavy metal ions, e.g. copper and iron, in the pathogenesis of PD through accelerating prion-like propagation of α-synuclein fibrils3.
Ca2+ has a causal role in controlling ROS production, a key pathological feature of PD. In MSA (multiple system atrophy) and LBD, Lewy bodies are primarily found in oligodendrocytes and cortical neurons, respectively4. The resulting influx of calcium ions appears to have two effects, one is increasing the release of dopamine and another neurotransmitter called acetylcholine — which deplete in Alzheimer’s and LBD — the other one is firing up the proteasome. Proteasome identifies and disposes misfolded proteins5.
Creutzfeldt Jakobs Disease (CJD)
Environmental pollution also is one of the cause of prions disease. There's an increase of CJD in Slovakia where manganese is a major pollutant. High Mn2+ levels and increased in Mn2+/Cu2+ ratios were observed in CJD brain, even at the cellular level there's a link of Mn2+ and prion infection6.
Magnetic Field
Reactive oxygen species (ROS) are a series of highly active radicals, irons and molecules that have a single unpaired electron in their outer shell, including free oxygen radicals. Excessive ROS could attack membrane phospholipids, impair mitochondrial function, and damage proteins, lipids, DNA, RNA, and sugar to disrupt normal cellular processes. Magnetic Fields (MFs) i.e. Static Magnetic Field (SMFs), Extremely Low Frequency Magnetic Field (ELF-EMF), and Radio Frequency Electromagnetic Radiation (RF-EMR) have potential damages to human health via increasing ROS in our cells. EMFs interaction with biological systems may cause oxidative stress under certain circumstances7.
The brain consumes the highest amount of oxygen in the human body and, although most oxygen is converted into CO2 and water, a small amount of O2 forms ROS. The high metabolic rate and the composition rich in polyunsaturated fatty acids which are ROS targets in brain, make brain more sensitive to oxidative damage. RF-EMR exposure could trigger depression of the antioxidant systems, due to increased lipid peroxidation and formation of free radicals. Thus glutathione and melatonin are good choices for decreasing the oxidative damage.
Free radicals can interact with DNA, leading to mutation, and interfere with gene regulation to eventually promote carcinogenesis. Another potential damage is in neuropathological conditions such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Redox reactive metals, such as iron, are leading causes of redox-generated hydroxyl radicals, and can promote the synthesis of amyloid beta (Aβ) precursor protein in an oxidative stress-mediated pathway. EMFs can increase the intracellular ion concentration levels, a molecular factor that positively correlates with the cleavage of the amyloid precursor protein to give the soluble Aβ thus favor the production of Aβ secreted in the bloodstream8.
Non-ions variables are also present in neurodegenerative disease and one of them is Glycine Zipper (GxxxG). The hydrophobic core of the Aβ sequence contains a GxxxG repeated motif, called glycine zipper, which involves crucial residues for assuring stability and promoting the process of fibril formation. The disruption of the glycine zipper is a possible strategy to reduce the aggregation of Aβ peptides9.
Glycine zipper is present in several viruses. In Hepatitis C virus (HCV), glycine zipper motifs within transmembrane helices 2 and 3 of NS4B that are critically involved in viral RNA replication. HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke10. HCV infection is reported to increase the risk of dementia, including Alzhemier's disease (AD), after adjusting for alcohol-related disease, liver cirrhosis, hepatitis encephalopathy, and hepatocellular carcinoma11.
Glycine Zipper is also found in SARS-CoV-2. SARS-CoV-2 spike proteins contain 5 GxxxG motifs in its sequence. One of the GxxxG sequences is present within its membrane fusion domain. Idrees and Kumar (2021) have proposed that the S1 component is prone to act as a functional amyloid and form toxic aggregates. It has the ability “to form amyloid and toxic aggregates that can act as seeds to aggregate many of the misfolded brain proteins and can ultimately lead to neurodegeneration. Tetz and Tetz (2020), reported that the form of the spike protein in SARS-CoV-2 has prion regions that are not present in the spike proteins for other coronaviruses. Classen (2021) proposed that the spike protein in the mRNA vaccines could cause prion-like diseases12. Anxiety disorders, insomnia, and dementia were reported in survivors of COVID-1913.
End.
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