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The Journal of Neuroscience, August 1, 2002, 22(15):6437-6446
Distribution of a Lysosomal Enzyme in the Adult Brain by Axonal
Transport and by Cells of the Rostral Migratory Stream
Marco A.
Passini,
Edward B.
Lee,
Gregory G.
Heuer, and
John
H.
Wolfe
Department of Pathobiology and Center for Comparative Medical
Genetics, School of Veterinary Medicine, University of Pennsylvania,
and Division of Neurology, Children's Hospital of Philadelphia,
Philadelphia, Pennsylvania 19104
A portion of the lysosomal enzymes produced by cells is
secreted, diffuses through extracellular spaces, and can be taken up by
distal cells via mannose-6-phosphate receptor-mediated endocytosis. This provides the basis for treating lysosomal storage diseases, many
of which affect the CNS. Normal enzyme secreted from a cluster of
genetically corrected cells has been shown to reverse storage lesions
in a zone of surrounding brain tissue in mouse disease models. However,
low levels of enzyme activity and reduction of storage lesions
also have been observed at sites in the brain that may not be
explained by a contiguous gradient of secreted enzyme diffusing
away from the genetically corrected cells. No direct evidence for
alternative mechanisms of enzyme transport has been shown, and little
is understood about the intracellular movement of lysosomal enzymes in
neurons. We investigated whether axonal transport could occur, by
expressing an eukaryotic lysosomal enzyme that can be visualized in
tissue sections ( -glucuronidase) in brain structures that have
defined axonal connections to other structures. This resulted in the
transfer of enzyme to, and a reversal of storage lesions in, neurons
that project to the gene expression site, but not in nearby structures
that would have been corrected if the effect had been mediated by
diffusion. In addition, transduction of cells in the subventricular
zone resulted in the uptake of -glucuronidase by cells entering the
rostral migratory stream. Gene transfer to specific neuronal circuits or cells in migratory pathways may facilitate delivery to the global
brain lesions found in these disorders.
Key words:
adeno-associated virus; -glucuronidase; septohippocampal system; axonal transport; rostral migratory stream; lysosomal storage disease; gene therapy
Copyright © 2002 Society for Neuroscience 0270-6474/02/22156437-10$05.00/0
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