Iron induces two distinct Ca²⁺ signalling cascades in astrocytes.

From Europe PMC via Jisc Publications RouterHistory: ppub 2021-05-01, epub 2021-05-05Publication status: PublishedFunder: National Natural Science Foundation of China (National Science Foundation of China); Grant(s): 81871852Iron is the fundamental element for numerous physiological functions. Plasmalemmal divalent metal ion transporter 1 (DMT1) is responsible for cellular uptake of ferrous (Fe2+), whereas transferrin receptors (TFR) carry transferrin (TF)-bound ferric (Fe3+). In this study we performed detailed analysis of the action of Fe ions on cytoplasmic free calcium ion concentration ([Ca2+]i) in astrocytes. Administration of Fe2+ or Fe3+ in μM concentrations evoked [Ca2+]i in astrocytes in vitro and in vivo. Iron ions trigger increase in [Ca2+]i through two distinct molecular cascades. Uptake of Fe2+ by DMT1 inhibits astroglial Na+-K+-ATPase, which leads to elevation in cytoplasmic Na+ concentration, thus reversing Na+/Ca2+ exchanger and thereby generating Ca2+ influx. Uptake of Fe3+ by TF-TFR stimulates phospholipase C to produce inositol 1,4,5-trisphosphate (InsP3), thus triggering InsP3 receptor-mediated Ca2+ release from endoplasmic reticulum. In summary, these findings reveal the mechanisms of iron-induced astrocytic signalling operational in conditions of iron overload

Genetic analysis of indel markers in three loci associated with Parkinson's disease

<div><p>The causal mutations and genetic polymorphisms associated with susceptibility to Parkinson’s disease (PD) have been extensively described. To explore the potential contribution of insertion (I)/deletion (D) polymorphisms (indels) to the risk of PD in a Chinese population, we performed genetic analyses of indel loci in <i>ACE</i>, <i>DJ-1</i>, and <i>GIGYF2</i> genes. Genomic DNA was extracted from venous blood of 348 PD patients and 325 age- and sex-matched controls without neurodegenerative disease. Genotyping of the indel loci was performed by fragment length analysis after PCR and DNA sequencing. Our results showed a statistically significant association for both allele <i>X</i> (alleles without <i>5</i>) vs. <i>5</i> (odds ratio = 1.378, 95% confidence interval = 1.112–1.708, <i>P</i> = 0.003) and genotype <i>5/X+X/X</i> vs. <i>5/5</i> (odds ratio = 1.681, 95% confidence interval = 1.174–2.407, <i>P</i> = 0.004) in the <i>GIGYF2</i> locus; however, no significant differences were detected for the <i>ACE</i> and <i>DJ-1</i> indels. After stratification by gender, no significant differences were observed in any indels. These results indicate that the <i>GIGYF2</i> indel may be associated with increased risk of PD in northern China.</p></div

Association study on indel locus of <i>GIGYF2</i> by gender stratification.

<p>Association study on indel locus of <i>GIGYF2</i> by gender stratification.</p

Frequency distribution and association analysis on indel locus of <i>GIGYF2</i> gene.

<p>Frequency distribution and association analysis on indel locus of <i>GIGYF2</i> gene.</p

Comparison of <i>GIGYF2</i> indel locus between male and female.

<p>Comparison of <i>GIGYF2</i> indel locus between male and female.</p

Nine allelic sequences were identified in the <i>GIGYF2</i> locus in this study.

<p>A6 (27.6%) is used as a reference sequence. Compared with A6, A5 (47.0%) and A7 (24.4%) were 3-bp repeated indels, and the others indels were different structural variations enclosing the poly-Q core unit (approximately 1.2%). The upper sequence represents base pairs of nucleic acids, and the lower sequence represents the corresponding amino acids.</p

The information of indel loci and PCR parameters.

<p>The information of indel loci and PCR parameters.</p

Association study on indel locus of <i>GIGYF2</i> by genotypic and allelic stratification.

<p>Association study on indel locus of <i>GIGYF2</i> by genotypic and allelic stratification.</p

Iatrogenic Iron Promotes Neurodegeneration and Activates Self-Protection of Neural Cells against Exogenous Iron Attacks

Metal implants are used worldwide, with millions of nails, plates, and fixtures grafted during orthopedic surgeries. Iron is the most common element of these metal implants. As time passes, implants can be corroded and iron can be released. Ionized iron permeates the surrounding tissues and enters circulation; importantly, iron ions pass through the blood-brain barrier. Can iron from implants represent a risk factor for neurological diseases? This remains an unanswered question. In this study, we discovered that patients with metal implants delivered through orthopedic surgeries have higher incidence of Parkinson's disease or ischemic stroke compared to patients who underwent similar surgeries but did not have implants. Concentration of serum iron and ferritin was increased in subjects with metal implants. In experiments in vivo, we found that injection of iron dextran selectively decreased the presence of divalent metal transporter 1 (DMT1) in neurons through increasing the expression of Ndfip1, which degrades DMT1 and does not exist in glial cells. At the same time, excess of iron increased expression of DMT1 in astrocytes and microglial cells and triggered reactive astrogliosis and microgliosis. Facing the attack of excess iron, glial cells act as neuroprotectors to accumulate more extracellular iron by upregulating DMT1, whereas neurons limit iron uptake through increasing DMT1 degradation. Cerebral accumulation of iron in animals is associated with impaired cognition, locomotion, and mood. Excess iron from surgical implants thus can affect neural cells and may be regarded as a risk factor for neurodegeneration.</p