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Molecular Pathophysiology Underlying Neuronal Ceroid Lipofuscinoses: Cln2 and Cln5

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Molecular Pathophysiology Underlying Neuronal Ceroid Lipofuscinoses: Cln2 and Cln5 MOLECULAR PATHOPHYSIOLOGY UNDERLYING NEURONAL CEROID LIPOFUSCINOSES: CLN2 AND CLN5 CARLOS JORGE PEREIRA BESSA Dissertação de doutoramento em Ciências Biomédicas 2009 Carlos Jorge Pereira Bessa Molecular Pathophysiology Underlying Neuronal Ceroid Lipofuscinoses: CLN2 and CLN5 Dissertação de Candidatura ao grau de Doutor em Ciências Biomédicas submetida ao Instituto de Ciências Biomédicas de Abel Salazar da Universidade do Porto. Orientador – Doutora Maria Gil Roseira Ribeiro Categoria – Técnica Superior de Saúde Afiliação – Instituto Nacional de Saúde Dr. Ricardo Jorge, Centro de Genética Médica Jacinto Magalhães Co-orientador – Doutor Jorge Eduardo da Silva Azevedo Categoria – Professor Catedrático Afiliação – Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto Legal precepts Preceitos legais In accord with the 2nd of the 8th article of Decreto-lei nº 388/70, the experimental results stated bellow in Publications I/II/III were used in this dissertation. The author of this dissertation declares his participation in the outlining and execution of the experimental work, in the data presentation and preparation of the work referenced below under the name Bessa, C / Carlos Bessa: De acordo com o disposto no nº2 do artigo 8º do Decreto-lei nº388/70, nesta dissertação foram utilizados os resultados dos trabalhos publicados abaixo referenciados. No cumprimento do disposto no referido Decreto-lei, o autor desta dissertação declara que interveio na concepção e execução do trabalho experimental, na interpretação e redacção dos resultados publicados sob o nome Bessa, C / Carlos Bessa: Publication I / Publicação I Bessa C, Teixeira CA, Dias A, Alves M, Rocha S, Lacerda L, Loureiro L, Guimarães A, Ribeiro MG. CLN2/TPP1 deficiency: the novel mutation IVS7-10A>G causes intron retention and is associated with a mild disease phenotype. Mol Genet Metab. 2008 Jan;93(1):66-73. Publication II / Publicação II Bessa C*, Teixeira CA*, Mangas M, Dias A, Sá Miranda MC, Guimarães A, Ferreira JC, Canas N, Cabral P, Ribeiro MG. Two novel CLN5 mutations in a Portuguese patient with vLINCL: insights into molecular mechanisms of CLN5 deficiency. Mol Genet Metab. 2006 Nov;89(3):245-53. * These authors contributed equally to the work. Publication III / Publicação III Mia-Lisa Schmiedt*, Carlos Bessa*, Claudia Heine, Maria Gil Ribeiro, Anu Jalanko, AiJa Kyttälä. The CLN5 protein: New insights into cellular processing and transport. 2009. Submitted. * These authors contributed equally to the work. This work received financial support from Fundação para a Ciência e Tecnologia (FCT), through a PhD fellowship (SFRH/BD/17560/2004), and from Vaincre les Maladies Lysosomales society. Este trabalho foi financiado pela Fundação para a Ciência e Tecnologia (FCT), através de uma bolsa de doutoramento (SFRH/BD/17560/2004), e pela associação Vaincre les Maladies Lysosomales. To my family Table of Contents 1 Abbreviations....................................................................................................12 2 Abstract..............................................................................................................15 3 Resumo..............................................................................................................17 4 Sommaire ..........................................................................................................20 5 Introduction.......................................................................................................22 6 Review of the literature.....................................................................................24 6.1 LYSOSOMES..........................................................................................................24 6.1.1 Structure and function of lysosomes......................................................................24 6.1.2 Biogenesis.............................................................................................................25 6.1.3 Trafficking of lysosomal proteins...........................................................................26 6.1.3.1 Mannose-6-phosphate dependent transport of soluble lysosomal proteins.........26 6.1.3.2 Mannose-6-phosphate independent transport of soluble lysosomal proteins......27 6.1.3.3 Transport of lysosomal membrane proteins.........................................................28 6.1.4 Lysosomal proteins and brain pathology...............................................................28 6.2 NEURONAL CEROID LIPOFUSCINOSIS...................................................................29 6.2.1 Common features in NCL......................................................................................30 6.2.2 Genetic heterogeneity............................................................................................31 6.2.3 NCL animal models................................................................................................33 6.2.4 Biological function of the NCL proteins..................................................................34 6.2.5 Molecular pathophysiology....................................................................................36 6.2.5.1 Apoptosis and autophagy....................................................................................36 6.2.5.2 Inflammation........................................................................................................37 6.2.5.3 The role of lipids..................................................................................................38 6.2.6 Therapeutic Strategies...........................................................................................39 6.3 LATE-INFANTILE NCL: CLN2 AND CLN5..................................................................40 6.3.1 Clinical phenotype and neuropathology.................................................................40 6.3.1.1 CLN2...................................................................................................................40 6.3.1.2 CLN5...................................................................................................................41 6.3.2 Genes and mutations.............................................................................................43 6.3.2.1 Classical Late-Infantile NCL................................................................................43 6.3.2.2 Finnish Late-Infantile Variant NCL.......................................................................44 6.3.3 The proteins...........................................................................................................45 6.3.3.1 TPP1...................................................................................................................45 6.3.3.2 CLN5p.................................................................................................................46 7 Aims of the Study..............................................................................................49 8 Materials and methods.....................................................................................50 9 Results ..............................................................................................................60 9.1 LINCL: EVIDENCE FOR MILD DISEASE DUE TO AN INTRON RETENTION DEFECT..61 9.1.1 Genotype identification..........................................................................................61 9.1.2 Predictions from in silico analysis..........................................................................62 9.1.3 Molecular consequences of the IVS7-10A>G mutation.........................................63 9.2 INSIGHTS INTO MOLECULAR MECHANISMS OF CLN5 DEFICIENCY.......................68 9.2.1 Identification of two novel CLN5 mutations underlying vLINCLFin..........................68 9.2.2 Impact of mutations on the mRNA and protein levels...........................................69 9.3 NOVEL INSIGHTS INTO THE BIOLOGICAL PROPERTIES OF CLN5..........................74 9.3.1 Analysis of N-terminal processing.........................................................................74 9.4 IMPACT OF MUTATIONS IN THE CELL BIOLOGY OF CLN5......................................79 9.4.1 Study of the intracellular trafficking and maturation of the CLN5 protein..............79 9.4.2 NCL-NCL protein interactions................................................................................81 10 General discussion and conclusions...........................................................83 11 References.......................................................................................................94 12 Online sources..............................................................................................112 13 Acknowledgments........................................................................................113 14 Appendix........................................................................................................117 1 Abbreviations aa amino acid(s) ANCL adult neuronal ceroid lipofuscinosis BFA brefeldin A bp base pair BSA bovine serum albumin CD-MPR cation dependent mannose-6-phosphate receptor cDNA complementary deoxyribonucleic acid CHX cycloheximide CI-MPR cation independent mannose-6-phosphate receptor CLN ceroid lipofuscinosis, neuronal (gene nomenclature) CLN ceroid lipofuscinosis, neuronal (protein nomenclature) CLN5 human ceroid lipofuscinosis, neuronal 5 protein Cln5 mouse ceroid lipofuscinosis, neuronal 5 protein CNS central nervous system COL R112H
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