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

doi:10.1073/pnas.0506473102

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

^*Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706; ^‡Department of Neurology, Jefferson Medical College, Philadelphia, PA 19107; and ^§Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010

Edited by Eric M. Shooter, Stanford University School of Medicine, Stanford, CA (received for review July 28, 2005)

Abstract

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.

Footnotes

↵ † To whom correspondence may be addressed at: 2015 Linden Drive, Madison, WI 53706. E-mail: kondoy{at}svm.vetmed.wisc.edu or duncani{at}svm.vetmed.wisc.edu.
Author contributions: Y.K. and I.D.D. designed research; Y.K. and V.G. performed research; Y.K. and D.A.W. analyzed data; and Y.K. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: CNP, 2′,3′-cyclic nucleotide 3′-phosphodiesterase; GALC, galactocerebrosidase; GLD, globoid cell leukodystrophy; MBP, myelin basic protein; OL, oligodendrocyte; OPC, oligodendrocyte progenitor cell; PNS, peripheral nervous system; shi, homozygous shiverer; twi, homozygous twitcher.
↵ ¶ Zhang, S. C., Wagner, D. & Duncan, I. D., 29th Annual Meeting of the Society for Neuroscience, Oct. 23-28, 1999, Miami Beach, FL (abstr.).
↵ ∥ Kondo, Y. & Duncan, I. D., 34th Annual Meeting of the Society for Neuroscience, Oct. 23-27, 2004, San Diego (abstr.).