MAPK dysregulation in the brain pathology of Mucopolysaccharidosis IIIB disease

Pag. 1 Background 2 1. Lysosomal storage disease 2 Pathogenetic events in lysosomal storage diseases 2 New therapeutic options for lysosomal storage diseases 5 Gene therapy by retroviral vectors 10 2. Mucopolysaccharidosis IIIB 14 Aims of the PhD thesis 16 Matherials and Methods 17 Chemicals 17 Animals 17 Western Blotting 17 Primary cortical neuronal cultures 18 Confocal immunofluorescence analysis 19 Measure of HS levels in cultured neurons 20 Statistical analysis 20 Results 21 Selective activation of ERK and JNK in the cortex of MPS IIIB mice 22 Selective downregulation of p38MAPK in the cortex of MPS IIIB mice 22 Primary cortical neurons: isolation and measure of GAGs levels 26 Activation of MAPKs in cultured neurons from MPS IIIB mice 26 Discussion 30 Conclusions 35 References 36 Acknowledgements 41 List of pubblications Villani GRD, Di Domenico C, Musella A, Cecere F, Di Napoli D, Di Natale P. Mucopolysaccharidosis IIIB: oxidative damage and cytotoxic cell involvement in the neuronal pathogenesis. Brain Research 2009;1279:99108. Visigalli I, Delai S, Politi LS, Di Domenico C, Cerri F, Mrak E, D'Isa R, Ungaro D, Stok M, Sanvito F, Mariani E, Staszewsky L, Godi C, Russo I, Cecere F, Del Carro U, Rubinacci A, Brambilla R, Quattrini A, Di Natale P, Ponder K, Naldini L, Biffi A. Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects Mucopolysaccharidosis type I phenotype in the mouse model. Blood, prepublished online September 16, 2010; DOI 10.1182/blood-2010-04278234.