Prevention of Lysosomal Storage in Tay-Sachs Mice Treated with N-Butyldeoxynojirimycin
Frances M. Platt,
*
Gabrielle R. Neises,
Gabriele Reinkensmeier,
Mandy J. Townsend,
V.
Hugh Perry,
Richard L. Proia,
Bryan Winchester,
Raymond A. Dwek,
Terry D. Butters
The glycosphingolipid (GSL) lysosomal storage diseases result from
the inheritance of defects in the genes encoding the enzymes required
for catabolism of GSLs within lysosomes. A strategy for the treatment
of these diseases, based on an inhibitor of GSL biosynthesis
N-butyldeoxynojirimycin, was evaluated in a mouse model of
Tay-Sachs disease. When Tay-Sachs mice were treated with N-butyldeoxynojirimycin, the accumulation of GM2
in the brain was prevented, with the number of storage neurons and the
quantity of ganglioside stored per cell markedly reduced. Thus,
limiting the biosynthesis of the substrate (GM2) for the
defective enzyme (
-hexosaminidase A) prevents GSL accumulation and
the neuropathology associated with its lysosomal storage.
F. M. Platt, G. Reinkensmeier, R. A. Dwek, T. D. Butters,
Glycobiology Institute, Department of Biochemistry, University of
Oxford, South Parks Road, Oxford 0X1 3QU, UK.
G. R. Neises, Monsanto Company, 700 Chesterfield Village Parkway, St.
Louis, MO 63198, USA.
M. J. Townsend and V. H. Perry, Department of Pharmacology, University
of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
R. L. Proia, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
B. Winchester, Institute of Child Health, 30 Guilford Street, London
WC1N 1EH, UK.
*
To whom correspondence should be addressed. E-mail:
fran{at}oxglua.glycob.ox.ac.uk
