Direct transfer of a lysosomal enzyme from lymphoid cells to deficient fibroblasts

Olsen, I; Dean, Michael F.; Harris, G.; Muir, Helen

doi:10.1038/291244a0

Cited by 72 publications

(31 citation statements)

References 22 publications

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“…4B), may indicate the presence of secreted GALC in the neuropil. In addition, direct cell-to-cell transfer of lysosomal enzyme independent of MPRs could be possible, because it occurs between lymphocytes and fibroblasts (27), although the phenomenon is enzyme-specific (28) and has not been tested for GALC or for OL-to-OL.…”

Section: Discussionmentioning

confidence: 99%

Galactocerebrosidase-deficient oligodendrocytes maintain stable central myelin by exogenous replacement of the missing enzyme in mice

Kondo

Wenger

Gallo

et al. 2005

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

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Globoid cell leukodystrophy (GLD) is a lysosomal storage disease caused by genetic deficiency of galactocerebrosidase (GALC) activity. Failure in catalyzing the degradation of its major substrate, galactocerebroside, in oligodendrocytes (OLs) and Schwann cells leads to death of these myelinating cells, progressive demyelination, and early demise of GLD patients. Transplantation of bone marrow cells and umbilical cord blood have been attempted as a means of enzyme replacement and have shown limited success. It remains unknown whether or how these therapies support survival of GALC-deficient OLs and myelin maintenance. We report that, upon transplantation, GALC-deficient OLs from the twitcher mouse, a model of GLD, achieved widespread myelination in the brain and spinal cord of the myelin-deficient shiverer mouse, which was preserved for the life of the host. GALC immunohistochemistry showed direct evidence for GALC transfer from the shiverer environment to the engrafted mutant OLs in vivo. These findings suggest that the mutant OLs can internalize exogenous GALC and maintain stable myelin, demonstrating that exogenous enzyme replacement will be a key strategy in the therapy of GLD.enzyme replacement ͉ globoid cell leukodystrophy ͉ myelination ͉ transplantation ͉ lysosomal storage disease G loboid cell leukodystrophy (GLD, also called Krabbe's disease) (1) is a lysosomal storage disease caused by genetic deficiency of activity of a lysosomal enzyme galactocerebrosidase (GALC) that catalyzes the digestion of its major substrate galactocerebroside in myelinating oligodendrocytes (OLs) and Schwann cells (2). GLD is characterized pathologically by rapidly progressive demyelination of the CNS and peripheral nervous system (PNS) and accumulation of macrophages in the demyelinating lesions. The majority of GLD patients (infantile form) succumb to severe neurological symptoms in the first two years of life.Homozygous twitcher (GALC twi/twi ; twi) mice (3) have a genetic defect in GALC activity (4, 5), show progressive demyelination and accumulation of macrophages in the CNS and PNS, and rarely survive Ͼ45 days. These similarities to GLD have enabled the mouse to serve as a bona fide model to explore the pathophysiology and therapy of GLD (6). It has recently been shown that twi OLs can internalize exogenous GALC in vitro, resulting in their phenotypic correction (7), raising the possibility that in vivo enzyme replacement could be used to treat GLD. However, it is essential to evaluate the effect of enzyme replacement on OL function in vivo, because in vitro correction cannot unequivocally determine the myelinating capacity of the cell or the longevity. Therefore, the aim of this study was to determine whether twi OLs form and maintain normal myelin when GALC is provided exogenously in the CNS. In search of a method of enzyme replacement in vivo, we transplanted twi mutant oligodendrocyte progenitor cells (OPCs) into the brain and spinal cord of homozygous shiverer (shi) mice in which OLs do not form compact myelin sheath...

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Section: Discussionmentioning

confidence: 99%

Galactocerebrosidase-deficient oligodendrocytes maintain stable central myelin by exogenous replacement of the missing enzyme in mice

Kondo

Wenger

Gallo

et al. 2005

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

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“…All tags (S, His, or thioredoxin) were removed using recombinant enterokinase (Novagen) in the case of pET32a-Trz1, whereas protein derived from pET29a-Trz1 includes the S-Tag. The 32 P-labeled yeast tRNA Ser was transcribed in vitro with T7 polymerase using a PCR template generated using primers SceSer3 (carrying a T7 promoter) and SceSer2 and plasmid pM11-tRNA CGA Ser (Olsen et al 1981). The tRNA Ser contains a 19-nt intron.…”

Section: In Vitro Processingmentioning

confidence: 99%

tRNA 3′ processing in yeast involves tRNase Z, Rex1, and Rrp6

Skowronek

Grzechnik

Späth

et al. 2013

RNA

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Mature tRNA 3 ′ ends in the yeast Saccharomyces cerevisiae are generated by two pathways: endonucleolytic and exonucleolytic. Although two exonucleases, Rex1 and Rrp6, have been shown to be responsible for the exonucleolytic trimming, the identity of the endonuclease has been inferred from other systems but not confirmed in vivo. Here, we show that the yeast tRNA 3 ′ endonuclease tRNase Z, Trz1, is catalyzing endonucleolytic tRNA 3 ′ processing. The majority of analyzed tRNAs utilize both pathways, with a preference for the endonucleolytic one. However, 3′ -end processing of precursors with long 3 ′ trailers depends to a greater extent on Trz1. In addition to its function in the nucleus, Trz1 processes the 3 ′ ends of mitochondrial tRNAs, contributing to the general RNA metabolism in this organelle.

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“…Certain lysosomal enzymes are transferred from normal lymphocytes to ¢broblasts from patients with lysosomal storage diseases [5]. Lymphocytes can play an important role in the transfer of corrective enzymes into cells throughout the body in the treatment of lysosomal diseases by bone marrow transplantation [6].…”

Section: Introductionmentioning

confidence: 99%

“…One is active internalization of the enzymes into lysosomes via mannose-6-phosphate receptor-mediated endocytosis [8]. A second, quite distinct process involves the transfer of certain lysosomal enzymes from lymphocytes to enzyme-de¢cient cells by cell-to-cell contact [5,7]. The e¤cacy of bone marrow transplantation to prevent and reverse the disease process varies from one lysosomal disorder to another [7], suggesting that complex and disease-speci¢c factors in transfer of di¡er-ent lysosomal enzymes are involved.…”

Section: Introductionmentioning

confidence: 99%

Human leukocyte glycosylasparaginase: cell‐to‐cell transfer and properties in correction of aspartylglycosaminuria

Dunder

Mononen

2001

FEBS Letters

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Aspartylglycosaminuria (AGU), a severe lysosomal storage disease, is caused by the deficiency of the lysosomal enzyme, glycosylasparaginase (GA), and accumulation of aspartylglucosamine (GlcNAc-Asn) in tissues. Here we show that human leukocyte glycosylasparaginase can correct the metabolic defect in Epstein^Barr virus (EBV)-transformed AGU lymphocytes rapidly and effectively by mannose-6-phosphate receptor-mediated endocytosis or by contact-mediated cell-to-cell transfer from normal EBV-transformed lymphocytes, and that 2^7% of normal activity is sufficient to correct the GlcNAc-Asn metabolism in the cells. Cell-to-cell contact is obligatory for the transfer of GA since normal transformed lymphocytes do not excrete GA into extracellular medium. The combined evidence indicates that cell-to-cell transfer of GA plays a main role in enzyme replacement therapy of AGU by normal lymphocytes. ß 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

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Direct transfer of a lysosomal enzyme from lymphoid cells to deficient fibroblasts

Cited by 72 publications

References 22 publications

Galactocerebrosidase-deficient oligodendrocytes maintain stable central myelin by exogenous replacement of the missing enzyme in mice

Galactocerebrosidase-deficient oligodendrocytes maintain stable central myelin by exogenous replacement of the missing enzyme in mice

tRNA 3′ processing in yeast involves tRNase Z, Rex1, and Rrp6

Human leukocyte glycosylasparaginase: cell‐to‐cell transfer and properties in correction of aspartylglycosaminuria

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