Pathogenesis of brain dysfunction in Batten disease

Walkley, Steven U.; March, Philip A.; Schroeder, Charles E.; Wurzelmann, Sarah; Jolly, R. D.

doi:10.1002/ajmg.1320570218

Cited by 38 publications

(13 citation statements)

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“…Lysosomes, containing hydrolytic enzymes, are responsible for breaking down obsolete intracellular materials during autophagy and degradation of extracellular macromolecules following endocytosis and phagocytosis [20]. Intracellular accumulation of 2Њ/3Њ lysosomes is closely associated with disease development, such as Fabry disease in heart and kidney [37] and Batten disease in brain neurons [38]. Human fibroblasts containing high amounts of 2Њ/3Њ lysosomes or lipopigments were more susceptible to oxidative stress and amino acid starvation [39,40], indicating that disturbance of important functions of the lysosomal system will result in adverse cytological effects.…”

Section: Discussionmentioning

confidence: 99%

Temporal changes of ethoxyresorufin‐O‐deethylase (EROD) activities and lysosome accumulation in intestine of fish on chronic exposure to dietary benzo[a]pyrene: Linking EROD induction to cytological effects

Yuen¹,

Au²

2006

Enviro Toxic and Chemistry

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Temporal changes of intestinal and hepatic ethoxyresorufin-O-deethylase (EROD) activities and quantitative changes of secondary and tertiary (e.g., 2 degrees/3 degrees) lysosomes in enterocytes were compared for the juvenile grouper (Epinephelus coioides) on chronic exposure to foodborne benzo[a]pyrene (BaP) at two environmentally realistic levels (0.25 and 12.5 microg/g fish/d) over a four-week exposure and four-week depuration period. Intestinal EROD induction was rapid (within 3 d) and sustained in the BaP-exposed fish, while a fast recovery (within one week) was observed on withdrawal of BaP intake. A dose-response relationship was demonstrated between intestinal EROD activities and the levels of foodborne BaP. Conversely, hepatic EROD induction was weak and subsided rapidly in the exposed fish, signifying that hepatic EROD activity is not a good indicator of oral intake of BaP. Significant increase of 2 degrees/3 degrees lysosomes, as measured by Vv(lysosome, mucosa), was detected in young enterocytes of fish in the high-dosing group (12.5 microg/g fish/d) at exposure day 3 and persisted until recovery week 2. Importantly, intestinal EROD activity was significantly correlated to 2 degrees/3 degrees lysosome accumulation in enterocytes (r = 0.571, p < 0.001). These results further corroborate our earlier findings that induction of EROD activities in fish do not merely indicate exposure to BaP but also are correlated to harmful biological effects. We recommend the use of these two biochemical and cytological changes in intestines as specific biomarkers to indicate current and recent exposure of fish to BaP via oral intake.

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Section: Discussionmentioning

confidence: 99%

Temporal changes of ethoxyresorufin‐O‐deethylase (EROD) activities and lysosome accumulation in intestine of fish on chronic exposure to dietary benzo[a]pyrene: Linking EROD induction to cytological effects

Yuen¹,

Au²

2006

Enviro Toxic and Chemistry

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“…Others were "aspiny" and lacked any evidence of dendritic spines or new synapse formation. Detailed studies of animal models of ganglioside storage diseases further revealed that both spiny and aspiny meganeurites could occur on specific populations of neurons, whereas in other diseases, like Batten disease (84,93), only aspiny meganeurites were found ( Figure 5). The issue was further complicated by the presence of some neurons exhibiting growth of ectopic dendritic membrane in the form of synapse-covered neuritic sprouts in the absence of a meganeurite.…”

Section: Meganeurite Formation In Storage Diseasesmentioning

confidence: 99%

Cellular Pathology of Lysosomal Storage Disorders

Walkley

1998

Brain Pathology

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137

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Lysosomal storage disorders are rare, inborn errors of metabolism characterized by intralysosomal accumulation of unmetabolized compounds. The brain is commonly a central focus of the disease process and children and animals affected by these disorders often exhibit progressively severe neurological abnormalities. Although most storage diseases result from loss of activity of a single enzyme responsible for a single catabolic step in a single organelle, the lysosome, the overall features of the resulting disease belies this simple beginning. These are enormously complex disorders with metabolic and functional consequences that go far beyond the lysosome and impact both soma-dendritic and axonal domains of neurons in highly neuron type-specific ways. Cellular pathological changes include growth of ectopic dendrites and new synaptic connections and formation of enlargements in axons far distant from the lysosomal defect. Other storage diseases exhibit neuron death, also occurring in a cell-selective manner. The functional links between known molecular genetic and enzyme defects and changes in neuronal integrity remain largely unknown. Future studies on the biology of lysosomal storage diseases affecting the brain can be anticipated to provide insights not only into these pathogenic mechanisms, but also into the role of lysosomes and related organelles in normal neuron function.

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“…3,4 Neuronal loss occurs in cerebral and cerebellar cortices, hippocampii and basal ganglia. 3,[5][6][7] Apoptosis, or programmed cell death type I (PCD I) [8][9][10]11 has been documented as chromatin condensation by EM, positive TUNEL staining and susceptibility of JNCL cells to apoptosis. 12,13 Apoptosis is amplified through the extrinsic or intrinsic pathway.…”

Section: Introductionmentioning

confidence: 99%