Lysosomal Disorders of the Brain: Recent Advances in Molecular and Cellular Pathogenesis and Treatment

Contents......Page 12
Plate Section......Page 478
List of contributors......Page 18
Prologue......Page 22
Section I Overview of lysosomes and storage diseases......Page 30
The endosomal–lysosomal system: the ‘early’ and ‘late’ endocytic compartments......Page 32
The endocytic process......Page 38
Itineraries of endocytosed molecules......Page 41
Trafficking through the endocytic recycling compartment......Page 46
Specialized aspects of endocytosis in neurones......Page 50
Summary......Page 52
References......Page 53
Introduction......Page 61
Traditional classification of lysosomal storage diseases......Page 62
Classifying lysosomal diseases on the basis of molecular defect......Page 68
Summary......Page 75
References......Page 76
General clinical presentation......Page 79
Specific clinical presentation and progression......Page 94
Summary......Page 103
References......Page 104
Section II Molecular mechanisms of storage......Page 108
Introduction......Page 110
Molecular genetics of lysosomal enzyme deficiencies......Page 111
Relating mutations to the structure and function of lysosomal enzymes......Page 112
Genotype/phenotype correlation in groups of neuronal storage disorders......Page 116
Summary......Page 144
References......Page 145
Clinical and biochemical background of multiple sulfatase deficiency......Page 160
Cα-Formylglycine in sulfatases......Page 161
Functional role of Cα-formylglycine......Page 162
Generation of Cα-formylglycine in the endoplasmic reticulum......Page 164
Structural determinants controlling Cα-formylglycine formation......Page 165
In vitro assay for Cα-formylglycine formation......Page 166
Purification of the Cα-formylglycine-generating system......Page 167
References......Page 168
Introduction......Page 170
Synthesis of N-acetylglucosamine-1-phospho-6-mannose diester groups in lysosomal enzymes......Page 171
The uncovering......Page 174
Mannose-6-phosphate-dependent packaging......Page 176
Defects and alterations in the mannose-6-phosphate-dependent targeting......Page 180
Mannose-6-phosphate-independent lysosomal targeting......Page 183
Dephosphorylation and degradation of lysosomal enzymes......Page 184
Summary......Page 187
References......Page 188
Introduction......Page 199
Molecular, biochemical, and structural properties of protective protein/cathepsin A......Page 200
Human protective protein/cathepsin A deficiency......Page 202
Pathology......Page 203
Molecular and biochemical defects......Page 204
Mouse model of galactosialidosis......Page 205
References......Page 210
Glycosphingolipid structure, function, and biosynthesis......Page 215
Lysosomal glycosphingolipid catabolism......Page 216
GM2 Activator protein......Page 219
Sphingolipid activator proteins derived from prosaposin......Page 222
Clinical aspects of activator protein deficiencies......Page 224
Pathophysiology of Niemann–Pick disease type C......Page 226
Summary......Page 227
References......Page 228
Introduction......Page 235
The endosomal/lysosomal v-ATPase......Page 237
Niemann–Pick C disease......Page 240
Neuronal ceroid lipofuscinoses—Batten disease......Page 243
Salla disease......Page 244
Danon disease......Page 245
Cystinosis......Page 246
Mucolipidosis type IV......Page 247
Summary......Page 248
References......Page 249
Section III Model systems and pathophysiological mechanisms......Page 258
Introduction......Page 260
Studies of orthologous proteins associated with lysosomal storage diseases......Page 261
Biogenesis and trafficking to the lysosome......Page 270
Proteins associated with disease and with lysosome biogenesis and their orthologues in model organisms......Page 275
Studies of orthologous proteins implicated in disease that are involved in lysosome biogenesis......Page 278
References......Page 279
Sphingolipidoses......Page 286
Glycogen lysosomal storage disorders......Page 295
Neuronal ceroid lipofuscinoses......Page 305
References......Page 308
A clinical maelstrom......Page 319
The pathogenic cascade in brain......Page 320
The why, where, and what of storage......Page 321
The cellular consequences of storage......Page 330
Functional assessment of brain......Page 341
References......Page 345
Section IV Treatment of storage diseases......Page 354
Enzyme replacement therapy is based on the process of endocytosis......Page 356
Endocytosis of lysosomal enzymes is receptor-mediated......Page 357
Early attempts at enzyme replacement were unsuccessful......Page 358
Enzyme replacement therapy is at various stages of development for several other lysosomal storage diseases......Page 359
General considerations for enzyme replacement in lysosomal storage disorders......Page 361
Can the blood–brain barrier be circumvented?......Page 362
Summary......Page 363
References......Page 364
Basic principles of cell-mediated therapy......Page 368
The challenges of the CNS and how CMT can address them......Page 369
Cross-correction in a dish......Page 371
Secretion studies in vitro......Page 373
Uptake and storage depletion......Page 377
Delivery of cells to the CNS......Page 379
Evidence of cross-correction within the CNS......Page 387
Anticipated advances and aspirations......Page 395
References......Page 397
Glycosphingolipids......Page 410
Biosynthesis of glycosphingolipids......Page 411
Glycosphingolipid storage diseases......Page 412
The pharmacological approach......Page 413
Imino sugars as enzyme activity modulators—chemical chaperone therapy......Page 419
How essential are glycosphingolipids in vivo?......Page 420
Evaluation of imino sugar inhibitors in models of glucosphingolipid storage diseases......Page 422
Prospects for combination therapy in Gaucher disease......Page 430
Summary......Page 431
References......Page 432
Introduction......Page 438
Therapeutic principle......Page 439
Gene therapy for lysosomal storage diseases affecting the brain......Page 440
Challenges and future directions......Page 451
Summary......Page 453
References......Page 454
A......Page 460
B......Page 461
C......Page 462
D......Page 463
E......Page 464
G......Page 465
K......Page 468
L......Page 469
M......Page 470
N......Page 471
P......Page 473
S......Page 474
T......Page 475
Y......Page 476