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- F-actin (1)
- Tdp-43 (1)
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- iron deficiency (1)
Protein inclusions containing the RNA-binding protein TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis and other neurodegenerative disorders. The loss of TDP-43 function that is associated with these inclusions affects post-transcriptional processing of RNAs in multiple ways including pre-mRNA splicing, nucleocytoplasmic transport, modulation of mRNA stability and translation. In contrast, less is known about the role of TDP-43 in axonal RNA metabolism in motoneurons. Here we show that depletion of Tdp-43 in primary motoneurons affects axon growth. This defect is accompanied by subcellular transcriptome alterations in the axonal and somatodendritic compartment. The axonal localization of transcripts encoding components of the cytoskeleton, the translational machinery and transcripts involved in mitochondrial energy metabolism were particularly affected by loss of Tdp-43. Accordingly, we observed reduced protein synthesis and disturbed mitochondrial functions in axons of Tdp-43-depleted motoneurons. Treatment with nicotinamide rescued the axon growth defect associated with loss of Tdp-43. These results show that Tdp-43 depletion in motoneurons affects several pathways integral to axon health indicating that loss of TDP-43 function could thus make a major contribution to axonal pathomechanisms in ALS.
Background
Iron deficiency (ID) is the leading cause of anemia worldwide. The prevalence of preoperative ID ranges from 23 to 33%. Preoperative anemia is associated with worse outcomes, making it important to diagnose and treat ID before elective surgery. Several studies indicated the effectiveness of intravenous iron supplementation in iron deficiency with or without anemia (ID(A)). However, it remains challenging to establish reliable evidence due to heterogeneity in utilized study outcomes. The development of a core outcome set (COS) can help to reduce this heterogeneity by proposing a minimal set of meaningful and standardized outcomes. The aim of our systematic review was to identify and assess outcomes reported in randomized controlled trials (RCTs) and observational studies investigating iron supplementation in iron-deficient patients with or without anemia.
Methods
We searched MEDLINE, CENTRAL, and ClinicalTrials.gov systematically from 2000 to April 1, 2022. RCTs and observational studies investigating iron supplementation in patients with a preoperative diagnosis of ID(A), were included. Study characteristics and reported outcomes were extracted. Outcomes were categorized according to an established outcome taxonomy. Quality of outcome reporting was assessed with a pre-specified tool. Reported clinically relevant differences for sample size calculation were extracted.
Results
Out of 2898 records, 346 underwent full-text screening and 13 studies (five RCTs, eight observational studies) with sufficient diagnostic inclusion criteria for iron deficiency with or without anemia (ID(A)) were eligible. It is noteworthy to mention that 49 studies were excluded due to no confirmed diagnosis of ID(A). Overall, 111 outcomes were structured into five core areas including nine domains. Most studies (92%) reported outcomes within the ‘blood and lymphatic system’ domain, followed by “adverse event” (77%) and “need for further resources” (77%). All of the latter reported on the need for blood transfusion. Reported outcomes were heterogeneous in measures and timing. Merely, two (33%) of six prospective studies were registered prospectively of which one (17%) showed no signs of selective outcome reporting.
Conclusion
This systematic review comprehensively depicts the heterogeneity of reported outcomes in studies investigating iron supplementation in ID(A) patients regarding exact definitions and timing. Our analysis provides a systematic base for consenting to a minimal COS.
Systematic review registration
PROSPERO CRD42020214247
Spontaneous Ca\(^{2+}\) transients and actin dynamics in primary motoneurons correspond to cellular differentiation such as axon elongation and growth cone formation. Brain-derived neurotrophic factor (BDNF) and its receptor trkB support both motoneuron survival and synaptic differentiation. However, in motoneurons effects of BDNF/trkB signaling on spontaneous Ca\(^{2+}\) influx and actin dynamics at axonal growth cones are not fully unraveled. In our study we addressed the question how neurotrophic factor signaling corresponds to cell autonomous excitability and growth cone formation. Primary motoneurons from mouse embryos were cultured on the synapse specific, β2-chain containing laminin isoform (221) regulating axon elongation through spontaneous Ca\(^{2+}\) transients that are in turn induced by enhanced clustering of N-type specific voltage-gated Ca\(^{2+}\) channels (Ca\(_{v}\)2.2) in axonal growth cones. TrkB-deficient (trkBTK\(^{-/-}\)) mouse motoneurons which express no full-length trkB receptor and wildtype motoneurons cultured without BDNF exhibited reduced spontaneous Ca\(^{2+}\) transients that corresponded to altered axon elongation and defects in growth cone morphology which was accompanied by changes in the local actin cytoskeleton. Vice versa, the acute application of BDNF resulted in the induction of spontaneous Ca\(^{2+}\) transients and Ca\(_{v}\)2.2 clustering in motor growth cones, as well as the activation of trkB downstream signaling cascades which promoted the stabilization of β-actin via the LIM kinase pathway and phosphorylation of profilin at Tyr129. Finally, we identified a mutual regulation of neuronal excitability and actin dynamics in axonal growth cones of embryonic motoneurons cultured on laminin-221/211. Impaired excitability resulted in dysregulated axon extension and local actin cytoskeleton, whereas upon β-actin knockdown Ca\(_{v}\)2.2 clustering was affected. We conclude from our data that in embryonic motoneurons BDNF/trkB signaling contributes to axon elongation and growth cone formation through changes in the local actin cytoskeleton accompanied by increased Ca\(_{v}\)2.2 clustering and local calcium transients. These findings may help to explore cellular mechanisms which might be dysregulated during maturation of embryonic motoneurons leading to motoneuron disease.