The neuropathogenic contributions of lysosomal dysfunction

• Published in: Journal of neurochemistry Vol. 83; no. 3; pp. 481 - 489
• Main Authors: Bahr, Ben A., Bendiske, Jennifer
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-11-2002; Blackwell
• Subjects: alpha-Synuclein; Alzheimer's disease; Amyloid - metabolism; amyloidogenic processing; Animals; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Humans; Huntingtin Protein; Lysosomal Storage Diseases, Nervous System - etiology; Lysosomal Storage Diseases, Nervous System - pathology; Lysosomal Storage Diseases, Nervous System - physiopathology; lysosomes; Lysosomes - metabolism; Lysosomes - pathology; Macromolecular Substances; Medical sciences; Nerve Tissue Proteins - metabolism; Neurodegenerative Diseases - etiology; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - physiopathology; Neurology; Nuclear Proteins - metabolism; Parkinson's disease; Protein Processing, Post-Translational; synaptic loss; Synucleins; tau; tau Proteins - metabolism; Human; Nervous system diseases; Parkinson's disease; Alzheimer disease; Pathogenesis; Deficiency; Parkinson disease; tau; Review; Lysosomal storage disease; Cerebral disorder; amyloidogenic processing; Tau protein; synaptic loss; Dysfunction; Central nervous system disease; Genetics; Degenerative disease; lysosomes; Mutation; Alzheimer's disease
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2002.01192.x

Multiple lines of evidence implicate lysosomes in a variety of pathogenic events that produce neurodegeneration. Genetic mutations that cause specific enzyme deficiencies account for more than 40 lysosomal storage disorders. These mostly pre‐adult diseases are associated with abnormal brain development and mental retardation. Such disorders are characterized by intracellular deposition and protein aggregation, events also found in age‐related neurodegenerative diseases including (i) Alzheimer's disease and related tauopathies (ii) Lewy body disorders and synucleinopathies such as Parkinson's disease, and (iii) Huntington's disease and other polyglutamine expansion disorders. Of particular interest for this review is evidence that alterations to the lysosomal system contribute to protein deposits associated with different types of age‐related neurodegeneration. Lysosomes are in fact highly susceptible to free radical oxidative stress in the aging brain, leading to the gradual loss of their processing capacity over the lifespan of an individual. Several studies point to this lysosomal disturbance as being involved in amyloidogenic processing, formation of paired helical filaments, and the aggregation of α‐synuclein and mutant huntingtin proteins. Most notably, experimentally induced lysosomal dysfunction, both in vitro and in vivo, recapitulates important pathological features of age‐related diseases including the link between protein deposition and synaptic loss.