Lysosomal disorders of the brain : recent advances in molecular and cellular pathogenesis and treatment / [edited by] Frances M. Platt and Steven U. Walkley.

Format:

Book

Contributor:

Platt, Frances M.

Walkley, Steven U.

Language:

English

Subjects (All):

Brain--Metabolism--Disorders.

Brain.

Brain--Metabolism--Disorders--Treatment.

Lysosomal storage diseases.

Lysosomal storage diseases--Treatment.

Lysosomal Storage Diseases, Nervous System--etiology.

Lysosomal Storage Diseases, Nervous System--therapy.

Brain--Metabolism.

Medical Subjects:

Lysosomal Storage Diseases, Nervous System--etiology.

Lysosomal Storage Diseases, Nervous System--therapy.

Physical Description:

xxvii, 447 pages, 8 unnumbered pages of plates : illustrations (some color) ; 25 cm

Place of Publication:

Oxford ; New York : Oxford University Press, 2004.

Summary:

Lysosomal storage diseases are inherited metabolic disorders characterized by severe pathology, typically involving the brain. Although individually rare, they collectively represent a significant group of diseases that primarily present in early infancy or childhood. In recent years considerable progress has been made in understanding the molecular mechanisms that lead to storage. Unravelling the basis for these diseases is providing unique insight into the normal biology of cells and pointing the way to the development of therapeutic strategies for their treatment. Lysosomal disorders of the brain details recent advances in the molecular and cellular pathologies of these diseases and in the development of effective therapies. After an overview of these diseases, the book describes the molecular mechanisms of storage, model systems and pathophysiological mechanisms, and finally, advice on treatment. With each chapter written by leading experts in their field, this book will be valuable for clinicians and scientists in helping them understand the mechanisms underlying these disorders, how they can be diagnosed, and what treatment options are currently available.

Contents:

Section I Overview of lysosomes and storage diseases

Chapter 1 The endosomal-lysosomal system / Frederick R. Maxfield, Sushmita Mukherjee 3

The endosomal-lysosomal system: the 'early' and 'late' endocytic compartments 3

The endocytic process 9

Itineraries of endocytosed molecules 12

Trafficking through the endocytic recycling compartment 17

Specialized aspects of endocytosis in neurones 21

Chapter 2 Lysosomal defects and storage / Frances M. Platt, Steven U. Walkley 32

Traditional classification of lysosomal storage diseases 33

Classifying lysosomal diseases on the basis of molecular defect 39

Chapter 3 Clinical aspects and diagnosis / J. Edmond Wraith 50

General clinical presentation 50

Specific clinical presentation and progression 65

Section II Molecular mechanisms of storage

Chapter 4 Primary defects in lysosomal enzymes / Bryan G. Winchester 81

Molecular genetics of lysosomal enzyme deficiencies 82

Relating mutations to the structure and function of lysosomal enzymes 83

Genotype/phenotype correlation in groups of neuronal storage disorders 87

Chapter 5 Defects in lysosomal enzyme modification for catalytic activity / Kurt von Figura, Ljudmila V. Borissenko, Jens Fey, Jianhe Peng, Bernhard Schmidt, Thomas Dierks 131

Clinical and biochemical background of multiple sulfatase deficiency 131

C[alpha]-Formylglycine in sulfatases 132

Functional role of C[alpha]-formylglycine 133

Generation of C[alpha]-formylglycine in the endoplasmic reticulum 135

Structural determinants controlling C[alpha]-formylglycine formation 136

In vitro assay for C[alpha]-formylglycine formation 137

Characterization of the C[alpha]-formylglycine-generating system 138

Purification of the C[alpha]-formylglycine-generating system 138

Chapter 6 Defects in lysosomal enzyme trafficking / Andrej Hasilik, Peter Lemansky 141

Synthesis of N-acetylglucosamine-1-phospho-6-mannose diester groups in lysosomal enzymes 142

The uncovering 145

Mannose-6-phosphate-dependent packaging 147

Defects and alterations in the mannose-6-phosphate-dependent targeting 151

Mannose-6-phosphate-independent lysosomal targeting 154

Dephosphorylation and degradation of lysosomal enzymes 155

Sequelae of targeting defects 158

Chapter 7 Defects in lysosomal enzyme protection: galactosialidosis / Alessandra d'Azzo 170

Protective protein/cathepsin A is a component of a lysosomal multi-enzyme complex 171

Molecular, biochemical, and structural properties of protective protein/cathepsin A 171

Protective protein/cathepsin A is a multifunctional protein 173

Human protective protein/cathepsin A deficiency 173

Pathology 174

Molecular and biochemical defects 175

Mouse model of galactosialidosis 176

Chapter 8 Defects in activator proteins and other soluble proteins of the lysosome / Oliver Macheleidt, Thomas Kolter, Konrad Sandhoff 186

Glycosphingolipid structure, function, and biosynthesis 186

Lysosomal glycosphingolipid catabolism 187

GM2 Activator protein 190

Sphingolipid activator proteins derived from prosaposin 193

Clinical aspects of activator protein deficiencies 195

Pathophysiology of Niemann-Pick disease type C 197

Chapter 9 Defects in transmembrane proteins / Yiannis A. Ioannou 206

The endosomal/lysosomal v-ATPase 208

Niemann-Pick C disease 211

Neuronal ceroid lipofuscinoses

Batten disease 214

Salla disease 215

Danon disease 216

Cystinosis 217

Mucolipidosis type IV 218

Section III Model systems and pathophysiological mechanisms

Chapter 10 Simple non-mammalian systems / David A. Pearce 231

Proteins associated with lysosomal storage diseases and their orthologues in model organisms 232

Studies of orthologous proteins associated with lysosomal storage diseases 232

Biogenesis and trafficking to the lysosome 241

Proteins associated with disease and with lysosome biogenesis and their orthologues in model organisms 246

Studies of orthologous proteins implicated in disease that are involved in lysosome biogenesis 249

Chapter 11 Spontaneous and engineered mammalian storage disease models / John J. Hopwood, Allison C. Crawley, Rosanne M. Taylor 257

Sphingolipidoses 257

Mucopolysaccharidoses 266

Glycoproteinoses 266

Glycogen lysosomal storage disorders 266

Mucolipidoses 276

Neuronal ceroid lipofuscinoses 276

Chapter 12 Pathogenic cascades and brain dysfunction / Steven U. Walkley 290

A clinical maelstrom 290

The pathogenic cascade in brain 291

The why, where, and what of storage 292

The cellular consequences of storage 301

Functional assessment of brain 312

Section IV Treatment of storage diseases

Chapter 13 Enzyme replacement therapy / Elizabeth F. Neufeld 327

Enzyme replacement therapy is based on the process of endocytosis 327

Endocytosis of lysosomal enzymes is receptor-mediated 328

Early attempts at enzyme replacement were unsuccessful 329

The first successful enzyme replacement therapy was treatment of type I Gaucher disease with macrophage-targeted glucocerebrosidase 330

Enzyme replacement therapy is at various stages of development for several other lysosomal storage diseases 330

General considerations for enzyme replacement in lysosomal storage disorders 332

Can the blood-brain barrier be circumvented? 333

Is there currently any role for enzyme replacement for lysosomal disorders with a neurologic component? 334

Chapter 14 Cell-mediated delivery systems / Kostantin Dobrenis 339

Basic principles of cell-mediated therapy 339

The challenges of the CNS and how CMT can address them 340

Cross-correction in a dish 342

Secretion studies in vitro 344

Uptake and storage depletion 348

Delivery of cells to the CNS 350

Evidence of cross-correction within the CNS 358

Anticipated advances and aspirations 366

Chapter 15 Inhibition of substrate synthesis: a pharmacological approach for glycosphingolipid storage disease therapy / Frances M. Platt, Terry D. Butters 381

Glycosphingolipids 381

Biosynthesis of glycosphingolipids 382

Glycosphingolipid storage diseases 383

Therapeutic options 384

The pharmacological approach 384

Imino sugars as enzyme activity modulators

chemical chaperone therapy 390

Potency, specificity, and cytotoxicity of imino sugars and PDMP series compounds 391

How essential are glycosphingolipids in vivo? 391

Glycosphingolipid depletion is tolerated in adult mice 393

Evaluation of imino sugar inhibitors in models of glucosphingolipid storage diseases 393

Prospects for combination therapy in Gaucher disease 401

Future compounds for substrate reduction therapy 402

Current status of studies evaluating substrate reduction therapy for glucosphingolipid storage diseases 402

Chapter 16 Gene therapy / Mark S. Sands 409

Barriers to effective therapy for central nervous system diseases 411

Gene therapy for lysosomal storage diseases affecting the brain 411

Challenges and future directions 422.

Notes:

Includes bibliographical references and index.

ISBN:

0198508786

OCLC:

55008555