Brain cell type-specific endocytosis of arylsulfatase A identifies limitations of enzyme-based therapies for metachromatic leukodystrophy.

Abstract

Enzyme replacement therapies, allogeneic bone marrow transplantation and gene therapies are treatment options for lysosomal storage diseases caused by inherited deficiencies of soluble lysosomal enzymes. Independent from the approach, the enzyme must be delivered to lysosomes of deficient patient cells. Little is known about the dissemination of enzyme within a tissue where cells compete for uptake via different receptor systems, binding affinities and endocytic rates. To evaluate dissemination and lysosomal targeting of a lysosomal enzyme in the CNS, we analysed receptor-mediated endocytosis of arylsulfatase A (ASA) by different types of brain-derived cell lines and primary murine brain cells. For ASA expressed by chinese hamster ovary cells for enzyme replacement therapy of metachromatic leukodystrophy, endocytic rates decline from microglia to neurons and astrocytes and to oligodendrocytes. Only immature oligodendrocytes endocytose significant amounts of enzyme. Uptake by non-microglial cells is due to mannose 6-phosphate receptors, whereas several receptor systems participate in endocytosis by microglial cells. Interestingly, ASA expressed by microglial cells cannot be taken up in a mannose 6-phosphate dependent manner. The resulting failure to correct non-microglial cells corroborates in vivo data and indicates that therapeutic effects of allogeneic bone marrow transplantation and hematopoietic stem cell gene therapy on metachromatic leukodystrophy are independent of metabolic cross-correction of neurons, astrocytes and oligodendrocytes by receptor-mediated endocytosis.

• Authors: Debora Kaminski, Claudia Yaghootfam, Frank Matthes, Annika Reßing, Volkmar Gieselmann, Ulrich Matzner
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 29 Issue 23 Pg. 3807-3817 (02 04 2021) ISSN: 1460-2083 [Electronic] England
• PMID: 33367737 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Cerebroside-Sulfatase

Topics

• Animals
• Astrocytes (metabolism, pathology)
• Brain (metabolism, pathology)
• Cerebroside-Sulfatase (genetics, metabolism)
• Endocytosis
• Enzyme Replacement Therapy (methods)
• Humans
• Leukodystrophy, Metachromatic (enzymology, pathology, therapy)
• Mice
• Microglia (metabolism, pathology)
• Oligodendroglia (metabolism, pathology)