Iron efflux from astrocytes plays a role in remyelination.
ABSTRACT How iron is delivered to the CNS for myelination is not well understood. We assessed whether astrocytes can provide iron to cells in the CNS for remyelination. To study this we generated a conditional deletion of the iron efflux transporter ferroportin (Fpn) in astrocytes, and induced focal demyelination in the mouse spinal cord dorsal column by microinjection of lysophosphatidylcholine (LPC). Remyelination assessed by electron microscopy was reduced in astrocyte-specific Fpn knock-out mice compared with wild-type controls, as was proliferation of oligodendrocyte precursor cells (OPCs). Cell culture work showed that lack of iron reduces the ability of microglia to express cytokines (TNF-α and IL-1β) involved in remyelination. Furthermore, astrocytes in culture express high levels of FGF-2 in response to IL-1β, and IGF-1 in response to TNF-α stimulation. FGF-2 and IGF-1 are known to be important for myelination. Reduction in IL-1β and IGF-1 were also seen in astrocyte-specific Fpn knock-out mice after LPC-induced demyelination. These data suggest that iron efflux from astrocytes plays a role in remyelination by either direct effects on OPCs or indirectly by affecting glial activation.
- SourceAvailable from: Yoshinori Tanaka[Show abstract] [Hide abstract]
ABSTRACT: IntroductionIt has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating lysosomal function. To elucidate the pathophysiological role of PGRN in the aged brain, in the present study, lysosomal function and pathological changes of the brain were investigated using 10- and 90-week-old wild-type and PGRN-deficient mice.ResultsWe showed that PGRN deficiency caused enhanced CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), in the aged brain. Immunoreactivity for Lamp1 (lysosome marker) in the VPM/VPL and expression of lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, and transcription factor EB genes, were also increased by PGRN deficiency. Aggregates of p62, which is selectively degraded by the autophagy-lysosomal system, were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. TAR DNA binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons were also observed in aged PGRN-deficient mice. PGRN deficiency caused enhanced expression of glial cell-derived cytotoxic factors such as macrophage expressed gene 1, cytochrome b-245 light chain, cytochrome b-245 heavy chain, complement C4, tumor necrosis factor-¿ and lipocalin 2. In addition, neuronal loss and lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice.Conclusions The present study shows that aged PGRN-deficient mice present with NCL-like pathology as well as TDP-43 aggregates in the VPM/VPL, where a particular vulnerability has been reported in NCL model mice. The present results also suggest that these pathological changes in the VPM/VPL are likely a result of lysosomal dysfunction. How PGRN prevents lysosomal dysfunction with aging remains to be elucidated.Acta neuropathologica communications. 07/2014; 2(1):78.
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ABSTRACT: Iron is an essential trophic element that is required for cell viability and differentiation, especially in oligodendrocytes, which consume relatively high rates of energy to produce myelin. Multiple iron metabolism proteins are expressed in the brain including transferrin receptor and ferritin-H. However, it is still unknown whether they are developmentally regulated in oligodendrocyte lineage cells for myelination. Here, using an in vitro cultured differentiation model of oligodendrocytes, we found that both transferrin receptor and ferritin-H are significantly upregulated during oligodendrocyte maturation, implying the essential role of iron in the development of oligodendrocytes. Additional different doses of Fe(3+) in the cultured medium did not affect oligodendrocyte precursor cell maturation or ferritin-H expression but decreased the expression of the transferrin receptor. These results indicate that upregulation of both transferrin receptor and ferritin-H contributes to maturation and myelination of oligodendrocyte precursor cells.Neural Regeneration Research 01/2013; 8(1):6-12. · 0.23 Impact Factor
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ABSTRACT: Controversy exists regarding the association between Iron Deficiency Anemia (IDA), iron status, and Febrile Convulsion (FC) during childhood. In this article, a systematic review and meta-analysis is conducted in order to determine possible association and the degree of association between these statuses and FC. To identify all studies related to IDA and FC, various references such as MEDLINE (PubMed), Embase (OVID), Web of sciences (Thomson Reuters) and Google scholar were searched (up until 15 January 2013). Heterogeneity was assessed using the Q statistic, Tau 2 , and I 2 . Additionally, subgroup analyses were performed. The outcome of primary interest was the overall Odds Ratio (OR) of FC for IDA and standard mean differences (SMD) of ferritin level. In total, 21 articles were considered to assess the association between IDA and FC. Anemia was more prevalent among the FC patients compared with the controls and the overall OR was 1.52 (95% CI=1.03 to 2.25). In addition, the pooled OR for 17 studies performed in the populations with low and moderate prevalence of anemia was 2.04 (95% CI=1.46 to 2.85). Furthermore, 12 studies assessed the association between the ferritin level and FC. The overall SMD was -0.02 with a 95% CI of -0.09 to 0.06. Besides, the pooled SMD of ferritin was -0.57 (95% CI=-0.7 to -0.46) in 6 studies reporting no difference between the FC and the control group with respect to temperature. IDA was associated with a moderate increased risk of FC in children, particularly in the areas with low and moderate prevalence of anemia.Iranian Journal of Medical Sciences 11/2014; 39(6).