Fugier C.,University of Strasbourg |
Klein A.F.,University Pierre and Marie Curie |
Hammer C.,University of Strasbourg |
Vassilopoulos S.,University Pierre and Marie Curie |
And 29 more authors.
Nature Medicine | Year: 2011
Myotonic dystrophy is the most common muscular dystrophy in adults and the first recognized example of an RNA-mediated disease. Congenital myotonic dystrophy (CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by the expression of mutant RNAs containing expanded CUG or CCUG repeats, respectively. These mutant RNAs sequester the splicing regulator Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the alternative splicing of other pre-mRNAs. We found that alternative splicing of the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of membranes and is required for the biogenesis of muscle T tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear myopathy, which shares some histopathological features with myotonic dystrophy. We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing. BIN1 missplicing results in expression of an inactive form of BIN1 lacking phosphatidylinositol 5-phosphate-"binding and membrane-tubulating activities. Consistent with a defect of BIN1, muscle T tubules are altered in people with myotonic dystrophy, and membrane structures are restored upon expression of the normal splicing form of BIN1 in muscle cells of such individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T tubule alterations and muscle weakness, a predominant feature of myotonic dystrophy. © 2011 Nature America, Inc. All rights reserved. Source
Castillo-Trivino T.,University of California at San Francisco |
Castillo-Trivino T.,Hospital Universitario Donostia |
Castillo-Trivino T.,Biodonostia Institute |
Braithwaite D.,University of California at San Francisco |
And 2 more authors.
PLoS ONE | Year: 2013
Background: Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS. Objectives: To evaluate the efficacy and safety of rituximab for MS treatment. Data collection: Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies. Main results: Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MS while the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-label rituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events. Author's conclusion: Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal. © 2013 Castillo-Trivino et al. Source
Riancho-Zarrabeitia L.,University of Cantabria |
Delgado-Alvarado M.,University of Cantabria |
Delgado-Alvarado M.,Biodonostia Institute |
Riancho J.,University of Cantabria |
And 8 more authors.
Clinical and Experimental Rheumatology | Year: 2014
Neurologic manifestations are found in 5-15 % of patients with sarcoidosis. This granulomatous disease may affect any part of the peripheral or the central nervous system, being potentially severe and difficult to treat. Corticosteroids are the cornerstone of therapy in sarcoidosis. However, some patients become resistant or experience side effects to corticosteroids. In these patients, second line therapies including immunosuppressive drugs such as methotrexate, azathioprine, mycophenolate, cyclophosphamide and leflunomide have been used. Anti-TNF-α drugs have been proposed as a therapeutic option for those who are refractory to immunosuppressive drugs or initially in cases of severe sarcoidosis. We report on 5 patients with neurosarcoidosis treated with anti-TNF-α drugs in our center. A literature review of patients with neurosarcoidosis treated with anti-TNF-α drugs was conducted. In our series successful response to anti-TNF-α therapy was achieved. However, the high frequency of relapses following anti-TNF-α discontinuation makes necessary a close follow-up of these patients when the biologic agent is stopped. © Clinical and Experimental Rheumatology 2014. Source
Manterola L.,Biodonostia Institute
Translational psychiatry | Year: 2013
1-42 β-Amyloid (Aβ(1-42)) peptide is a key molecule involved in the development of Alzheimer's disease. Some of its effects are manifested at the neuronal morphological level. These morphological changes involve loss of neurites due to cytoskeleton alterations. However, the mechanism of Aβ(1-42) peptide activation of the neurodegenerative program is still poorly understood. Here, Aβ(1-42) peptide-induced transduction of cellular death signals through the phosphatidylinositol 3-kinase (PI3K)/phosphoinositol-dependent kinase (PDK)/novel protein kinase C (nPKC)/Rac 1 axis is described. Furthermore, pharmacological inhibition of PDK1 and nPKC activities blocks Rac 1 activation and neuronal cell death. Our results provide insights into an unsuspected connection between PDK1, nPKCs and Rac 1 in the same signal-transduction pathway and points out nPKCs and Rac 1 as potential therapeutic targets to block the toxic effects of Aβ(1-42) peptide in neurons. Source
Lopez de Maturana R.,Laboratory of Stem Cells and Neural Repair |
Aguila J.C.,Laboratory of Stem Cells and Neural Repair |
Sousa A.,Laboratory of Stem Cells and Neural Repair |
Vazquez N.,Laboratory of Stem Cells and Neural Repair |
And 8 more authors.
Neurobiology of Aging | Year: 2014
Inflammatory mechanisms are activated in aging and late-onset neurodegenerative diseases, such as Parkinson's disease (PD). Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to both idiopathic and familial forms of PD. Here, we investigated the involvement of LRRK2 in inflammatory pathways using primary dermal fibroblasts from patients with 2 common mutations in LRRK2 (G2019S and R1441G), idiopathic PD and age-matched healthy individuals. Basal cyclooxygenase (COX)-2 RNA levels were very high in the fibroblasts of all patients. Remarkably, LRRK2 silencing experiments significantly reduced basal COX-2 levels and COX-2 induction after a pro-inflammatory stimulus. Additionally, in samples from patients with the R1441G mutation and with idiopathic PD, we found a prominent cytoplasmic re-distribution of human antigen R, a protein that, among others, stabilizes COX-2 RNA. Furthermore, the response to lipopolysaccharide was defective in these 2 groups, which showed weak induction of pro-inflammatory cytokines and reduced NFκB transcriptional activation. In summary, we describe multiple defects in inflammatory pathways in which LRRK2 appears to be critically involved. Further studies are required to establish the therapeutic implications of inflammatory dysregulation in the pathophysiology of Parkinson's disease. © 2014 Elsevier Inc. Source