Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a \u3cem\u3eDrosophila\u3c/em\u3e model of Fus-mediated ALS

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease characterized by the loss of motor function. Several ALS genes have been identified as their mutations can lead to familial ALS, including the recently reported RNA-binding protein fused in sarcoma (Fus). However, it is not clear how mutations of Fus lead to motor neuron degeneration in ALS. In this study, we present a Drosophila model to examine the toxicity of Fus, its Drosophila orthologue Cabeza (Caz), and the ALS-related Fus mutants. RESULTS: Our results show that the expression of wild-type Fus/Caz or FusR521G induced progressive toxicity in multiple tissues of the transgenic flies in a dose- and age-dependent manner. The expression of Fus, Caz, or FusR521G in motor neurons significantly impaired the locomotive ability of fly larvae and adults. The presynaptic structures in neuromuscular junctions were disrupted and motor neurons in the ventral nerve cord (VNC) were disorganized and underwent apoptosis. Surprisingly, the interruption of Fus nuclear localization by either deleting its nuclear localization sequence (NLS) or adding a nuclear export signal (NES) blocked Fus toxicity. Moreover, we discovered that the loss of caz in Drosophila led to severe growth defects in the eyes and VNCs, caused locomotive disability and NMJ disruption, but did not induce apoptotic cell death. CONCLUSIONS: These data demonstrate that the overexpression of Fus/Caz causes in vivo toxicity by disrupting neuromuscular junctions (NMJs) and inducing apoptosis in motor neurons. In addition, the nuclear localization of Fus is essential for Fus to induce toxicity. Our findings also suggest that Fus overexpression and gene deletion can cause similar degenerative phenotypes but the underlying mechanisms are likely different

Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS

<p>Abstract</p> <p>Backgound</p> <p>Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease characterized by the loss of motor function. Several ALS genes have been identified as their mutations can lead to familial ALS, including the recently reported RNA-binding protein fused in sarcoma (Fus). However, it is not clear how mutations of Fus lead to motor neuron degeneration in ALS. In this study, we present a <it>Drosophila </it>model to examine the toxicity of Fus, its <it>Drosophila </it>orthologue Cabeza (Caz), and the ALS-related Fus mutants.</p> <p>Results</p> <p>Our results show that the expression of wild-type Fus/Caz or FusR521G induced progressive toxicity in multiple tissues of the transgenic flies in a dose- and age-dependent manner. The expression of Fus, Caz, or FusR521G in motor neurons significantly impaired the locomotive ability of fly larvae and adults. The presynaptic structures in neuromuscular junctions were disrupted and motor neurons in the ventral nerve cord (VNC) were disorganized and underwent apoptosis. Surprisingly, the interruption of Fus nuclear localization by either deleting its nuclear localization sequence (NLS) or adding a nuclear export signal (NES) blocked Fus toxicity. Moreover, we discovered that the loss of <it>caz </it>in <it>Drosophila </it>led to severe growth defects in the eyes and VNCs, caused locomotive disability and NMJ disruption, but did not induce apoptotic cell death.</p> <p>Conclusions</p> <p>These data demonstrate that the overexpression of Fus/Caz causes <it>in vivo </it>toxicity by disrupting neuromuscular junctions (NMJs) and inducing apoptosis in motor neurons. In addition, the nuclear localization of Fus is essential for Fus to induce toxicity. Our findings also suggest that Fus overexpression and gene deletion can cause similar degenerative phenotypes but the underlying mechanisms are likely different.</p

Artemisinin derivative SM934, influences the activation, proliferation, differentiation and antibody-secreting capacity of β-cells in systemic lupus erythematosus mice via inhibition of TLR7/9 signaling pathway

Purpose: To study the influence of artemisinin derivative, SM934 on activation, proliferation, differentiation and antibody-secreting capacity of B cells of systemic lupus erythematosus (SLE) mice, and the underlying mechanism. Methods: Female MRL/lpr mice (n = 60) were randomly assigned to four groups of 15 mice each: SLE, 2.5 mg/kg SM934; 5 mg/kg SM934, and 10 mg/kg SM934 groups. Serum levels of interleukins 6, 10, 17 and 21 (IL-6, IL-17, IL-10 and IL-21) were determined. The secretions of immunoglobulins G and M (IgG and IgM) by B cells were determined. The population of B lymphocyte subtypes was determined flow cytometrically. The expressions of Blimp-1 and Bcl-6, Toll-like receptors 7 and 9 (TLR7 and TLR9) mRNAs were determined. Results: SLE-induced upregulation of serum IL-10, IL-6, IL-17 and IL-21 was significantly and dosedependently reduced following a 2-month treatment with SM934 (p &lt; 0.01). Treatment with SM934 significantly and dose-dependently accentuated B cell germinal center B cell populations, but significantly and dose-dependently decreased the populations of plasma and activated B cells (p &lt; 0.01). The splenic levels of IgG and IgM were decreased in a dose-dependent fashion after 8 weeks of treatment (p &lt; 0.01). Artemisinin derivative SM934 decreased the expression of Blimp-1, and upregulated the expression of Bcl-6, both in a dose-dependent manner (p &lt; 0.01). Moreover, SM934 decreased the mRNA expressions of TLR7 and TLR9 in a dose-based manner (p &lt; 0.01). Conclusion: Artemisinin derivative SM934 mitigates LSE syndromes by suppressing the TLR-induced B-cell stimulation and plasma cell generatio

Higher vitamin B6 dietary consumption is associated with a lower risk of glaucoma among United States adults

ObjectiveAlthough numerous studies have substantiated the neuroprotective effects of vitamin B6 on the optic nerve and its enhancement of visual function, comprehensive data delineating the correlation between vitamin B6 and glaucoma at a national demographic scale remain insufficient. This study is designed to explore the link between the dietary consumption of vitamin B6 and glaucoma.MethodsThis study included 3,850 individuals aged 40 and older from the National Health and Nutrition Examination Survey (NHANES), spanning 2005–2008. Dietary consumption of vitamin B6 was calculated from the average of two 24-h dietary recall interviews. Glaucoma was diagnosed in accordance with the established Rotterdam criteria. To evaluate the relationship between vitamin B6 dietary consumption and the risk of glaucoma, we employed Restricted Cubic Splines and weighted multivariable logistic regression analysis. We employed stratified and three other sensitivity analyses to confirm the robustness of our results, and conducted a preliminary exploration of the potential association between vitamin B6 supplement consumption and glaucoma risk.ResultsAfter adjusting for covariates, we found a significant inverse correlation between dietary consumption of vitamin B6 and glaucoma risk (pnon-linearity = 0.18; p for trend = 0.02). Stratified analysis and three other sensitivity analyses revealed stability in the outcomes (all p for interaction&gt;0.05). Compared to the lowest quartile of consumption (≤1.23 mg/day), individuals in the highest quartile of vitamin B6 consumption (&gt;2.34 mg/day) experienced a 75% reduction in glaucoma risk (OR = 0.25, 95% CI 0.07–0.92). However, the effect of vitamin B6 supplements on glaucoma was inconclusive.ConclusionA diet high in vitamin B6 inversely correlates with glaucoma risk, suggesting that increasing dietary intake of vitamin B6 could be a viable preventative strategy against glaucoma among adults in the United States

Molecular Cloning and Response to Water Temperature and Nutrient Manipulation of Insulin-like Growth Factor (IGF) Genes in Golden Pompano Trachinotus ovatus (Linnaeus 1758) Larvae

In this study, insulin-like growth factor I (IGF I) and IGF II in golden pompano larvae were cloned and analyzed. In the first trial, IGF expression during ontogeny of larvae in the first 18-days of their life was explored, and then the response of IGFs to water temperature (23, 26, and 29oC) on 12 day post hatching (DPH) and 18 DPH were compared. On 28 DPH, the response of IGFs to the manipulation of nutrients was evaluated. The expression of IGF I increased with the increase of fish age, and was not significantly affected by water temperature. The expression of IGF II was affected by water temperature on 12 DPH and 18 DPH. The expression of IGF II at 23oC was significantly higher than at 26oC and 29oC. The expression of IGFs in fish larvae on 28 DPH was not concomitant with nutrient manipulation. This study detected the gene expression of IGFs at the early stage of golden pompano larvae. The time dependent expression of IGF genes in fish larvae is important to understand the ontogenetic development and growth of fish larvae in early life