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Gaucher disease is caused by a deficiency of glucocerebrosidase. Patients with Gaucher disease are divided into three major phenotypes: chronic nonneuronopathic, acute neuronopathic, and chronic neuronopathic, based on symptoms of the nervous system, the severity of symptoms, and the age of disease onset. The characteristics of patients with acute neuronopathic- and chronic neuronopathic type Gaucher disease include oculomotor abnormalities, bulbar signs, limb rigidity, seizures and occasional choreoathetoid movements, and neuronal loss. However, the mechanisms leading to the neurodegeneration of this disorder remain unknown. To investigate brain dysfunction in Gaucher disease, we studied the possible role of inflammation in neurodegeneration during development of Gaucher disease in a mouse model. Elevated levels of the proinflammatory cytokines, IL-1α, IL-1β, IL-6, and TNF-α, were detected in the fetal brains of Gaucher mice. Moreover, the levels of secreted nitric oxide and reactive oxygen species in the brains of Gaucher mice were higher than in wild-type mice. Thus, accumulated glucocerebroside or glucosylsphingosine, caused by glucocerebrosidase deficiency, may mediate brain inflammation in the Gaucher mouse via the elevation of proinflammatory cytokines, nitric oxide, and reactive oxygen species.

miRGator is an integrated database of microRNA (miRNA)-associated gene expression, target prediction, disease association and genomic annotation, which aims to facilitate functional investigation of miRNAs. The recent version of miRGator v2.0 contains information about (i) human miRNA expression profiles under various experimental conditions, (ii) paired expression profiles of both mRNAs and miRNAs, (iii) gene expression profiles under miRNA-perturbation (e.g. miRNA knockout and overexpression), (iv) known/predicted miRNA targets and (v) miRNA-disease associations. In total, >8000 miRNA expression profiles, ∼300 miRNA-perturbed gene expression profiles and ∼2000 mRNA expression profiles are compiled with manually curated annotations on disease, tissue type and perturbation. By integrating these data sets, a series of novel associations (miRNA–miRNA, miRNA–disease and miRNA–target) is extracted via shared features. For example, differentially expressed genes (DEGs) after miRNA knockout were systematically compared against miRNA targets. Likewise, differentially expressed miRNAs (DEmiRs) were compared with disease-associated miRNAs. Additionally, miRNA expression and disease-phenotype profiles revealed miRNA pairs whose expression was regulated in parallel in various experimental and disease conditions. Complex associations are readily accessible using an interactive network visualization interface. The miRGator v2.0 serves as a reference database to investigate miRNA expression and function (http://miRGator.kobic.re.kr).

BackgroundMutations in heat shock 27 kDa protein 1 (HSP27 or HSPB1) cause distal hereditary motor neuropathy (dHMN) or Charcot-Marie-Tooth disease type 2 F (CMT2F) according to unknown factors. Mutant HSP27 proteins affect axonal transport by reducing acetylated tubulin.ResultsWe generated a transgenic mouse model overexpressing HSP27-S135F mutant protein driven by Cytomegalovirus (CMV) immediate early promoter. The mouse phenotype was similar to dHMN patients in that they exhibit motor neuropathy. To determine the phenotypic aberration of transgenic mice, behavior test, magnetic resonance imaging (MRI), electrophysiological study, and pathology were performed. Rotarod test showed that founder mice exhibited lowered motor performance. MRI also revealed marked fatty infiltration in the anterior and posterior compartments at calf level. Electrophysiologically, compound muscle action potential (CMAP) but not motor nerve conduction velocity (MNCV) was reduced in the transgenic mice. Toluidine staining with semi-thin section of sciatic nerve showed the ratio of large myelinated axon fiber was reduced, which might cause reduced locomotion in the transgenic mice. Electron microscopy also revealed abundant aberrant myelination. Immunohistochemically, neuronal dysfunctions included elevated level of phosphorylated neurofilament and reduced level of acetylated tubulin in the sural nerve of transgenic mice. There was no additional phenotype besides motor neuronal defects.ConclusionsOverexpression of HSP27-S135F protein causes peripheral neuropathy. The mouse model can be applied to future development of therapeutic strategies for dHMN or CMT2F.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-015-0154-y) contains supplementary material, which is available to authorized users.

BackgroundFabry disease is characterised by the progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in vascular endothelial cells. Enzyme replacement therapy (ERT) clears this accumulation. We analysed plasma proteome profiles before and after ERT to characterise its molecular pathology.MethodsTwo-dimensional electrophoresis and matrix-assisted laser desorption/ionisation-time of flight tandem mass spectrometry (MALDI-TOF MS) and tandem mass spectrometry (MS/MS) were done using plasma samples before and after ERT in eight patients with classical Fabry diseaseResultsAfter short-term ERT (4–12 months), the levels of 15 plasma proteins involved in inflammation, oxidative and ischaemic injury, or complement activation were reduced significantly. Among them, β-actin (ACTB), inactivated complement C3b (iC3b), and C4B were elevated significantly in pre-ERT Fabry disease plasma compared with control plasma. After longer-term ERT (46–96 months), iC3b levels gradually decreased, whereas the levels of other proteins varied. The gradual reduction of iC3b was comparable to that of Gb3 levels. In addition, iC3b increased significantly in pre-ERT Fabry disease mouse plasma, and C3 deposits were notable in renal tissues of pre-enzyme replacement therapy patients.ConclusionThese results indicated that C3-mediated complement activation might be altered in Fabry disease and ERT might promote its stabilisation.