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San Sebastián de los Reyes, Spain

Otaegui D.,Experimental Unit | Querejeta R.,Hospital Donostia | Arrieta A.,Experimental Unit | Lazkano A.,University of the Basque Country | And 4 more authors.
Molecular and Cellular Biochemistry | Year: 2010

Phospholipase C-β (PLCβ) isozymes (PLCβ1 and PLCβ3) have been extensively characterized in cardiac tissue, but no data are available for the PLCβ4 isozyme. In this study, PLCβ(1-4) isozymes mRNA relative expression was studied by real-time PCR (RT-PCR) in human, rat, and murine left ventricle and the presence of PLCβ4 isozyme at the protein level was confirmed by Western blotting in all species studied. Confocal microscopy experiments carried out in HL-1 cardiomyocytes revealed a sarcoplasmic subcellular distribution of PLCβ4. Although there were unexpected significant interspecies differences in the PLCβ(1-4) mRNA expression, PLCβ4 mRNA was the main transcript expressed in all left ventricles studied. Thus, whereas in human and rat left ventricles PLCβ4 > PLCβ3 > PLCβ2 > PLCβ1 mRNA pattern of expression was found, in murine left ventricle the pattern of expression was different, i.e., PLCβ4 > PLCβ1 > PLCβ3 > PLCβ 2. However, results obtained in mouse HL-1 cardiomyocytes showed PLCβ3 ≈ PLCβ4 > PLCβ1 > PLCβ2 pattern of mRNA expression indicating a probable cell type specific expression of the different PLCβ isozymes in cardiomyocytes. Finally, RT-PCR experiments showed a trend, even though not significant (P = 0.067), to increase PLCβ4 mRNA levels in HL-1 cardiomyocytes after angiotensin II treatment. These results demonstrate the presence of PLCβ4 in the heart and in HL-1 cardiomyocytes showing a different species-dependent pattern of expression of the PLCβ (1-4) transcripts. We discuss the relevance of these findings in relation to the development of cardiac hypertrophy. © 2009 Springer Science+Business Media, LLC. Source

Sistiaga A.,Experimental Unit | Urreta I.,Epidemiology Unit | Jodar M.,Autonomous University of Barcelona | Cobo A.M.,Association Francaise contre les Myopathies | And 7 more authors.
Psychological Medicine | Year: 2010

Background Although central nervous system (CNS) involvement in adult myotonic dystrophy type 1 (DM1) was described long ago, the large number of variables affecting the cognitive and personality profile have made it difficult to determine the effect of DM1 on the brain. The aim of this study was to define the cognitive and personality patterns in adult DM1 patients, and to analyse the relationship between these clinical patterns and their association with the underlying molecular defect.Method We examined 121 adult DM1 patients with confirmed molecular CTG repeat expansion and 54 control subjects using comprehensive neuropsychological tests and personality assessments with the Millon Clinical Multiaxial Inventory (MCMI)-II. We used a multiple linear regression model to assess the effect of each variable on cognition and personality adjusted to the remainders.Results Patients performed significantly worse than controls in tests measuring executive function (principally cognitive inflexibility) and visuoconstructive ability. In the personality profile, some paranoid and aggressive traits were predominant. Furthermore, there was a significant negative correlation between the CTG expansion size and many of the neuropsychological and personality measures. The molecular defect also correlated with patients' daytime somnolence.Conclusions Besides muscular symptomatology, there is significant CTG-dependent involvement of the CNS in adult DM1 patients. Our data indicate that the cognitive impairment predominantly affects the fronto-parietal lobe. © 2009 Cambridge University Press. Source

Dhaenens C.M.,French Institute of Health and Medical Research | Dhaenens C.M.,University of Lille Nord de France | Tran H.,French Institute of Health and Medical Research | Tran H.,University of Lille Nord de France | And 38 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2011

Tau is the proteinaceous component of intraneuronal aggregates common to neurodegenerative diseases called Tauopathies, including myotonic dystrophy type 1. In myotonic dystrophy type 1, the presence of microtubule-associated protein Tau aggregates is associated with a mis-splicing of Tau. A toxic gain-of-function at the ribonucleic acid level is a major etiological factor responsible for the mis-splicing of several transcripts in myotonic dystrophy type 1. These are probably the consequence of a loss of muscleblind-like 1 (MBNL1) function or gain of CUGBP1 and ETR3-like factor 1 (CELF1) splicing function. Whether these two dysfunctions occur together or separately and whether all mis-splicing events in myotonic dystrophy type 1 brain result from one or both of these dysfunctions remains unknown. Here, we analyzed the splicing of Tau exons 2 and 10 in the brain of myotonic dystrophy type 1 patients. Two myotonic dystrophy type 1 patients showed a mis-splicing of exon 10 whereas exon 2-inclusion was reduced in all myotonic dystrophy type 1 patients. In order to determine the potential factors responsible for exon 10 mis-splicing, we studied the effect of the splicing factors muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1), CUGBP1 and ETR3-like factor 2 (CELF2), and CUGBP1 and ETR3-like factor 4 (CELF4) or a dominant-negative CUGBP1 and ETR-3 like factor (CELF) factor on Tau exon 10 splicing by ectopic expression or siRNA. Interestingly, the inclusion of Tau exon 10 is reduced by CUGBP1 and ETR3-like factor 2 (CELF2) whereas it is insensitive to the loss-of-function of muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1) gain-of-function, or a dominant-negative of CUGBP1 and ETR-3 like factor (CELF) factor. Moreover, we observed an increased expression of CUGBP1 and ETR3-like factor 2 (CELF2) only in the brain of myotonic dystrophy type 1 patients with a mis-splicing of exon 10. Taken together, our results indicate the occurrence of a mis-splicing event in myotonic dystrophy type 1 that is induced neither by a loss of muscleblind-like 1 (MBNL1) function nor by a gain of CUGBP1 and ETR3-like factor 1 (CELF1) function but is rather associated to CUGBP1 and ETR3-like factor 2 (CELF2) gain-of-function. © 2011 Elsevier B.V. Source

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