The metabolism of Tay-Sachs ganglioside: catabolic studies with lysosomal enzymes from normal and Tay-Sachs brain tissue

Tallman, John F.; Johnson, William G.; Brady, Roscoe O.

doi:10.1172/jci107045

Cited by 57 publications

(12 citation statements)

References 25 publications

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“…1). The observed high specific activity of b-hexosaminidase (2,700-3,300 units), as compared to other enzymes in brain tissue, may explain the metabolic significance of this enzyme with respect to the catabolism of gangliosides [29]. Except for carboxyl esterase activity localized mainly in microsomes, which was found to be comparable between the pineal gland and rest of the brain regions, other hydrolytic enzymes studied were found to be several folds higher in pineal gland.…”

Section: Discussionmentioning

confidence: 78%

Activity of Hydrolytic Enzymes in Various Regions of Normal Human Brain Tissue

2012

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The activity of six hydrolytic enzymescarboxyl esterase, acid phosphatase, alkaline phosphatase, b-galactosidase, b-glucosidase and b-hexosaminidase, were studied in different regions of the normal human brain tissue obtained at autopsy. Protein estimation and activities of the hydrolytic enzymes with respective substrates were assayed by spectrophotometric and spectroflourometric methods. Amongst the eight regions of the brain-frontal, parietal, occipital, temporal, thalamus, cerebellum and hippocampus, the pineal gland showed highest activity for all hydrolytic enzymes studied except for carboxyl esterase. Among six hydrolases studied, hexosaminidase exhibited highest activity in all regions of the human brain while alkaline phosphatase activity was the least amongst all regions studied. A majority of the enzymes studied showed higher activity in gray matter as compared to the white matter except acid phosphatase and b-glucosidase which exhibited higher activity in the white matter. The most significant finding in the present study was the high activity of all hydrolytic enzymes noted in the pineal gland as compared to all other regions of the human brain. Such a finding has not been hitherto reported earlier in human brain tissue samples. If the specific activities of these enzymes are to be considered as any functional index, then pineal gland may be more metabolically active tissue with respect to the hydrolytic function as compared to the other regions of the brain.

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Section: Discussionmentioning

confidence: 78%

Activity of Hydrolytic Enzymes in Various Regions of Normal Human Brain Tissue

2012

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“…However, even when given under these conditions, only 0.6% of the administered dose ofenzyme (2000 ng) entered the brain. Using this delivery fraction, we estimate that :100 milligrams of enzyme would be required to achieve a normal concentration ofenzyme in brain (20). It is probable, however, that this degree of enzyme replacement may not be necessary to achieve significant mobilization of the substrate (GM2) ganglioside in the pathological state.…”

Section: Discussionmentioning

confidence: 99%

Delivery of hexosaminidase A to the cerebrum after osmotic modification of the blood--brain barrier.

Neuwelt¹,

Barranger²,

Brady³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

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The present studies were undertaken to evaluate the possibility that hexosaminidase A, the enzyme-deficient in Tay-Sachs disease, could be effectively delivered to brain. Previous studies from our laboratory have shown that hypertonic mannitol can be used to osmotically produce reversible disruption of the blood-brain barrier in animals (rat and dog) and man without significant neurotoxicity and that such barrier modification significantly increases the delivery ofcytoreductive chemotherapy agents to selected areas ofbrain. By using the rat model of bloodbrain barrier modification and radiolabeled enzyme, increased hexosaminidase A delivery to brain has been demonstrated in more than 85 animals. The time of injection of hexosaminidase A after blood-brain barrier disruption is critical for maximum delivery. Rapid (over 30 sec) intra-arterial administration of hexosaminidase A immediately after blood-brain barrier disruption resulted in a marked increase in enzyme delivery to the brain when compared with controls without prior barrier disruption. When the enzyme was administered 15-20 min after barrier disruption, -50% less hexosaminidase A was delivered; when given 60-120 min after barrier modification, the amount delivered was the same as in control animals. This critical time course is very different than that seen in trials of low molecular weight chemotherapeutic agents (methotrexate and adriamycin). These preliminary studies suggest that hexosaminidase A can be delivered to the brain by blood-brain barrier modification and may be indicative of the potential for enzyme replacement in patients who have Tay-Sachs disease.

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“…Once the etiology of Gaucher disease was established, the enzymatic defects in other hereditary metabolic storage disorders were rapidly elucidated. These included Niemann-Pick disease in 1966 (26); Fabry disease in 1967 (27), and Tay-Sachs disease in 1969 (28,29). Practical benefit soon followed.…”

Section: Journal Of Biological Chemistry 41217mentioning

confidence: 99%