The loss of functional Survival Motor Neuron (SMN) protein due to mutations or deletion in the SMN1 gene causes autosomal recessive neurodegenerative spinal muscle atrophy (SMA). A potential treatment strategy for SMA is to upregulate the amount of SMN protein originating from the highly homologous SMN2 gene, compensating in part for the absence of the functional SMN1 gene. We have previously shown that in vitro activation of the p38 pathway stabilizes and increases SMN mRNA levels leading to increased SMN protein levels. In this report, we explore the impact of the p38 activating, FDA-approved, blood brain barrier permeating compound celecoxib on SMN levels in vitro and in a mouse model of SMA. We demonstrate a significant induction of SMN protein levels in human and mouse neuronal cells upon treatment with celecoxib. We show that activation of the p38 pathway by low doses celecoxib increases SMN protein in a HuR protein-dependent manner. Furthermore, celecoxib treatment induces SMN expression in brain and spinal cord samples of wild-type mice in vivo. Critically, celecoxib treatment increased SMN levels, improved motor function and enhanced survival in a severe SMA mouse model. Our results identify low dose celecoxib as a potential new member of the SMA therapeutic armamentarium.
The neuronal apoptosis inhibitory protein (NAIP) is a constituent of the inflammasome and a key component of the innate immune system. Here we use immunofluorescence to position NAIP within the cytokinetic apparatus, contiguous to chromosomal passenger complex (CPC), Centralspindlin, PRC1 and KIF4A. During metaphase, NAIP accumulates in the mitotic spindle poles and is shown in spindle microtubules; in anaphase NAIP is detected in the middle of the central spindle. At the end of cytokinesis, NAIP is localized in the outlying region of the stem body, the center of the intercellular bridge formed between daughter cells prior to cellular abscission. We also describe the sustained presence of NAIP mRNA and protein throughout the cell cycle with a significant increase observed in the G2/M phase. Consistent with a role for NAIP in cytokinesis, NAIP overexpression in HeLa cells promotes the acquisition of a multinuclear phenotype. Conversely, NAIP siRNA gene silencing results in an apoptotic lethal phenotype. Our confocal and super resolution stimulated-emission-depletion (STED) examination of mammalian cell cytokinesis demonstrate a potential new role for NAIP in addition to anti-apoptotic and innate immunology functions.
BackgroundSpinal Muscular Atrophy (SMA) is one of the most common inherited causes of infant death and is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. One of the treatment strategies for SMA is to induce the expression of the protein from the homologous SMN2 gene, a rescuing paralog for SMA.Methods and resultsHere we demonstrate the promise of pharmacological modulation of SMN2 gene by BAY 55-9837, an agonist of the vasoactive intestinal peptide receptor 2 (VPAC2), a member of G protein coupled receptor family. Treatment with BAY 55-9837 lead to induction of SMN protein levels via activation of MAPK14 or p38 pathway in vitro. Importantly, BAY 55-9837 also ameliorated disease phenotype in severe SMA mouse models.ConclusionOur findings suggest the VPAC2 pathway is a potential SMA therapeutic target.
Studies of peripheral blood lymphocytes (PBL) and plasma from patients with malignant lymphoma [Hodgkin's disease (HD) and non Hodgkin's lymphoma (NHL)] show that plasma soluble interleukin 2 receptor (sIL2R) levels are closely linked with disease status [normal volunteers (n = 15) 402 +/- 158 u/ml; patients with Hodgkin's disease in remission (n = 4) 525 +/- 195 u/ml or with active disease (n = 11) 3026 +/- 1602 u/ml (p < 0.001); patients with non Hodgkin's lymphoma in remission (n = 6) 462 +/- 202 u/ml, active disease (n = 15) 2713 +/- 1755 u/ml, (p < 0.001)] but no correlation between sIL2R and the inhibition of interleukin 2 (IL2) generated cytotoxicity for the cell line K562. In only 1 of 15 patient plasma samples studied was there a dose dependent inhibition of IL2 generated cell killing. In a further patient, IL2 generated K562 killing was inhibited at all doses (500-3000 brmp units/ml); treatment of this plasma with anti-Interleukin 4 (alpha IL4) had no effect on the potent inhibitory activity of the plasma. Plasma sIL2R levels were markedly elevated in patients receiving IL2 in vivo (pre treatment 520 +/- 170 IU/ml, during treatment 5578 +/- 2564 IU/ml, p = 0.05). The aetiology of immunosuppression in patients with lymphoma appears to be multi-factorial; although sIL2R correlates with disease activity it does not appear to directly mediate immunosuppression in most patients with malignant lymphoma.
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