De Lemos L.,University of Barcelona |
Junyent F.,University of Barcelona |
Junyent F.,Rovira i Virgili University |
Verdaguer E.,University of Barcelona |
And 6 more authors.
Journal of Neurochemistry | Year: 2010
The MAPK family is formed by extracellular signal-regulated kinases p38 kinase and stress-activated protein kinases (SAPK/JNK). There are three genes that encode for three JNK proteins. JNK3 is mainly expressed in the central nervous system and has been related to various processes in that tissue. Specifically, JNK3 plays a crucial role in neuronal death in several neurodegenerative diseases. The activation of this kinase has been described in epilepsy, Alzheimer's disease, Parkinson's disease and Huntington's disease. Different studies have shown that the lack of the Jnk3 gene confers neuroprotection. However, the specific mechanism involved in such neuroprotection has not yet been elucidated. Therefore, in the present study, we analyzed the neuroprotection in mice lacking Jnk3 against neuronal death induced by kainic acid. Moreover, we analyzed the activation of different MAPKs. The results revealed that neuronal death was attenuated and different activation/inactivation of p38 and extracellular signal-regulated kinases 1/2 was reported with respect to control. Therefore, the data indicate that the lack of the JNK3 protein modulates other MAPKs and these changes could also have a pivotal role in neuroprotection. © 2010 International Society for Neurochemistry.
Berger J.,Medical University of Vienna |
Pujol A.,Institute Of Neuropatologia |
Pujol A.,Catalan Institution for Research and Advanced Studies |
Aubourg P.,University of Paris Descartes |
Forss-Petter S.,Medical University of Vienna
Brain Pathology | Year: 2010
Mutations in the ABCD1 gene cause the clinical spectrum of the neurometabolic disorder X-linked adrenoleukodystrophy/adrenomyeloneuropathy (X-ALD/AMN). Currently, the most efficient therapeutic opportunity for patients with the cerebral form of X-ALD is hematopoietic stem cell transplantation and possibly gene therapy of autologous hematopoietic stem cells. Both treatments, however, are only accessible to a subset of X-ALD patients, mainly because of the lack of markers that can predict the onset of cerebral demyelination. Moreover, for female or male X-ALD patients with AMN, currently only unsatisfying therapeutic opportunities are available. Thus, this review focuses on current and urgently needed future pharmacological therapies. The treatment of adrenal and gonadal insufficiency is well established, whereas applications of immunomodulatory and immunosuppressive drugs have failed to prevent progression of cerebral neuroinflammation. The use of Lorenzo's oil and the inefficacy of lovastatin to normalize very-long-chain fatty acids in clinical trials as well as currently experimental and therefore possible future therapeutic strategies are reviewed. The latter include pharmacological gene therapy mediated by targeted upregulation of ABCD2, the closest homolog of ABCD1, antioxidative drug treatment, small molecule histone deacetylase inhibitors such as butyrates and valproic acid, and other neuroprotective attempts. © 2010 International Society of Neuropathology.
Yubero D.,Institute Dinvestigacio Sanitaria Sant Joan Of Deu |
Brandi N.,University of Barcelona |
Ormazabal A.,Institute Dinvestigacio Sanitaria Sant Joan Of Deu |
Ormazabal A.,Institute Salud Carlos III |
And 54 more authors.
PLoS ONE | Year: 2016
Background: Next-generation sequencing (NGS) technology has allowed the promotion of genetic diagnosis and are becoming increasingly inexpensive and faster. To evaluate the utility of NGS in the clinical field, a targeted genetic panel approach was designed for the diagnosis of a set of inborn errors of metabolism (IEM). The final aim of the study was to compare the findings for the diagnostic yield of NGS in patients who presented with consistent clinical and biochemical suspicion of IEM with those obtained for patients who did not have specific biomarkers. Methods: The subjects studied (n = 146) were classified into two categories: Group 1 (n = 81), which consisted of patients with clinical and biochemical suspicion of IEM, and Group 2 (n = 65), which consisted of IEM cases with clinical suspicion and unspecific biomarkers. A total of 171 genes were analyzed using a custom targeted panel of genes followed by Sanger validation. Results: Genetic diagnosis was achieved in 50% of patients (73/146). In addition, the diagnostic yield obtained for Group 1 was 78% (63/81), and this rate decreased to 15.4% (10/65) in Group 2 (χ2 = 76.171; p < 0.0001). Conclusions: A rapid and effective genetic diagnosis was achieved in our cohort, particularly the group that had both clinical and biochemical indications for the diagnosis. © 2016 Yubero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Malfatti E.,Institut Universitaire de France |
Malfatti E.,University of Siena |
Malfatti E.,French Institute of Health and Medical Research |
Malfatti E.,University Pierre and Marie Curie |
And 32 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2013
FHL1 mutations have been associated with various disorders that include reducing body myopathy (RBM), Emery-Dreifuss-like muscular dystrophy, isolated hypertrophic cardiomyopathy, and some overlapping conditions. We report a detailed histochemical, immunohistochemical, electron microscopic, and immunoelectron microscopic analyses of muscle biopsies from 18 patients carrying mutations in FHL1: 14 RBM patients (Group 1), 3 Emery-Dreifuss muscular dystrophy patients (Group 2), and 1 patient with hypertrophic cardiomyopathy and muscular hypertrophy (Group 2). Group 1 muscle biopsies consistently showed RBs associated with cytoplasmic bodies. The RBs showed prominent FHL1 immunoreactivity whereas desmin, αB-crystallin, and myotilin immunoreactivity surrounded RBs. By electron microscopy, RBs were composed of electron-dense tubulofilamentous material that seemed to spread progressively between the myofibrils and around myonuclei. By immunoelectron microscopy, FHL1 protein was found exclusively inside RBs. Group 2 biopsies showed mild dystrophic abnormalities without RBs; only minor nonspecific myofibrillar abnormalities were observed under electron microscopy. Molecular analysis revealed missense mutations in the second FHL1 LIM domain in Group 1 patients and ins/del or missense mutations within the fourth FHL1 LIM domain in Group 2 patients. Our findings expand the morphologic features of RBM, clearly demonstrate the localization of FHL1 in RBs, and further illustrate major morphologic differences among different FHL1-related myopathies. © 2013 by the American Association of Neuropathologists, Inc.
Liu J.,University of Kentucky |
Liang S.,University of Kentucky |
Liu X.,University of Kentucky |
Brown J.A.,University of Kentucky |
And 9 more authors.
Journal of Lipid Research | Year: 2012
ABCD2 (D2) is a peroxisomal transporter that is highly abundant in adipose tissue and promotes the oxidation of long-chain MUFA. Erucic acid (EA, 22:1ω9) reduces very long chain saturated fatty acids in patients with X-linked adrenoleukodystrophy but promotes dyslipidemia and dilated cardiomyopathy in rats. To determine the role of D2 in the metabolism of EA, we challenged wild-type and D2 defi- cient mice (D2 KO) with an enriched EA diet. In D2 KO mice, dietary EA resulted in the rapid expansion of adipose tissue, adipocyte hypertrophy, hepatic steatosis, and the loss of glycemic control. However, D2 had no impact on the development of obesity phenotypes in two models of diet-induced obesity. Although there was a significant increase in EA in liver of D2 KO mice, it constituted less than 2% of all fatty acids. Metabolites of EA (20:1, 18:1, and 16:1) were elevated, particularly 18:1, which accounted for 50% of all fatty acids. These data indicate that the failure to metabolize EA in adipose results in hepatic metabolism of EA, disruption of the fatty acid profile, and the development of obesity and reveal an essential role for D2 in the protection from dietary EA. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc.