Lysosomal glycogen storage mimicking the cytological picture of Pompe’s disease as induced in rats by injection of an α-glucosidase inhibitor

Lüllmann‐Rauch, Renate

doi:10.1007/bf02892847

Cited by 23 publications

(2 citation statements)

References 21 publications

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“…Since the high-molecular-weight glycogen is built on a protein backbone (Krisman & Barengo, 1975;Geddes & Stratton, 1977b;Chee & Geddes, 1977;, and in fact may be distinguished from its low-molecular-weight counterpart by its high protein content (Chee & Geddes, 1977), it would seem likely that the synthesis and packaging of the large glycogen particles into the lysosomes proceeds by a process similar to that used in the synthesis of glycoprotein (Palade, 1975;Lodish et al, 1980). Our results show that disturbance of normal processing at a later stage of the pathway (illustrated by Lullman- Rauch, 1982, Fig. lOa) results in the accumulation particularly of low-molecular-weight glycogen, which the normal phosphorolytic pathway, without external hormonal stimulus (Cohen, 1982), fails to clear.…”

Section: Discussionmentioning

confidence: 63%

Disturbance of lysosomal glycogen metabolism by liposomal anti-alpha-glucosidase and some anti-inflammatory drugs

Geddes¹,

Otter²,

Scott³

et al. 1983

Biochemical Journal

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The size-distribution of liver glycogen was shown to be distinctly affected by the anti-inflammatory drugs salicylate and indomethacin. By measurement of the incorporation of radioactive glucose into glycogen, salicylate was shown to have a depressing effect on overall liver glycogen metabolism. These effects appear to arise from the stabilizing of the lysosome by the drugs. The incorporation, via liposomes, of purified anti-1,4-alpha-glucosidase activity and in the content of high-molecular-weight glycogen. These changes are increased by prolonged liposomal antibody treatment and suggest that a possible feedback control mechanism operates in the incorporation of glycogen into lysosomes. These experiments may be useful as a model of glycogen turnover and its failure in glycogenosis type II (Pompe's disease).

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Section: Discussionmentioning

confidence: 63%

Disturbance of lysosomal glycogen metabolism by liposomal anti-alpha-glucosidase and some anti-inflammatory drugs

Geddes¹,

Otter²,

Scott³

et al. 1983

Biochemical Journal

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“…The authors concluded that the cytologic picture resembled that of type II glycogenosis. Intralysosomal glycogen storage was also prominent in kidney, adrenal cortex, and spleen (12). Removal of the inhibitor resulted in a slow recovery.…”

Section: Resultsmentioning

confidence: 97%

Castanospermine inhibits alpha-glucosidase activities and alters glycogen distribution in animals.

Saul¹,

Ghidoni²,

Molyneux³

et al. 1985

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

126

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Castanospermine, an inhibitor of a-glucosidase activity, was injected into rats to determine its effects in vivo. Daily injections of alkaloid, at levels of 0.5 mg/g of body weight, or higher, for 3 days decreased hepatic a-glucosidase to 40% of control values, whereas a-glucosidase in brain was reduced to 25% of control values and that in spleen and kidney was reduced to about 40%. In liver, both the neutral (pH 6.5) and the acidic (pH 4.5) a-glucosidase activities were inhibited, but the former was more susceptible. On the other hand, 13-Nacetylhexosaminidase activity was elevated in the livers of treated animals, whereas f8-galactosidase activity was unchanged and a-mannosidase activity was somewhat inhibited. Livers of treated animals were examined by light and electron microscopy and compared to control animals to determine whether changes in morphology had occurred. In treated animals fed normal rat chow, the hepatocytes were smaller in size and simplified in structure, whereas the high-glucose diet lessened these alterations. Furthermore, in those animals receiving castanospermine at 1.0 mg or higher per g of body weight for 3 days, there was a marked decrease in the amount of glycogen in the cytoplasm, while a large number of lysosomes were observed that were full of dense, granular material. That this dense material was indeed glycogen was shown by the fact that it disappeared when blocks of fixed tissue were pretreated with a-amylase. Glycogen levels in liver, as measured either colorimetrically or enzymatically, were somewhat depressed at the higher levels of castanospermine.Castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine) is an indolizine alkaloid that is found in the seeds of the Australian tree Castanospermum australe (1). These seeds have been reported to be toxic to animals and to cause various symptoms, including gastrointestinal upset. We recently found that this alkaloid was a potent inhibitor of lysosomal a-and ,3-glucosidase but had no effect on a number of other glycosidases (2). In addition, castanospermine also inhibits the neutral glucosidase(s) that participates in the processing of the oligosaccharide chains of the N-linked glycoproteins (3). Thus, in cultured mammalian cells, castanospermine prevents the formation of complex chains and gives rise to glycoproteins having mostly Glc3Man7_9GlcNAc2 structures.Since glucosidases are very important enzymes in a number of metabolic sequences, including glycogen degradation, we were interested in determining whether this alkaloid would affect glycogen metabolism if injected into animals. Based on preliminary experiments, we postulated that castanospermine would inhibit the lysosomal a-glucosidase and produce a lysosomal block leading to the abnormal storage of glycogen. The data presented in this paper show that this alkaloid markedly depressed the activity levels of a-glucosidase in liver and other tissues. Coupled with this decreased activity was the finding that the livers of rats given this alkaloid for several days had...

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History and Morphology of the Lysosome

Lüllmann‐Rauch

Lysosomes

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Lysosomal glycogen storage mimicking the cytological picture of Pompe’s disease as induced in rats by injection of an α-glucosidase inhibitor

Cited by 23 publications

References 21 publications

Disturbance of lysosomal glycogen metabolism by liposomal anti-alpha-glucosidase and some anti-inflammatory drugs

Disturbance of lysosomal glycogen metabolism by liposomal anti-alpha-glucosidase and some anti-inflammatory drugs

Castanospermine inhibits alpha-glucosidase activities and alters glycogen distribution in animals.

History and Morphology of the Lysosome

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