Journal
JOURNAL OF NEUROSCIENCE
Volume 27, Issue 35, Pages 9482-9490Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2287-07.2007
Keywords
arylsulfatase A; cerebroside sulfotransferase; lysosomal storage disorder; metachromatic leukodystrophy; myelin; sulfatide
Categories
Ask authors/readers for more resources
Metachromatic leukodystrophy ( MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A ( ASA). This results in accumulation of sulfated glycosphingolipids, mainly 3-O-sulfogalactosylceramide ( sulfatide), in the nervous system and various other organs. In patients, lipid storage causes a progressive loss of myelin leading to various neurological symptoms. The sulfatide storage pattern in ASA-deficient [ ASA( -/-)] mice is comparable to humans, but regrettably, the mice do not mimic the myelin pathology. We reasoned that increasing sulfatide storage in this animal model might provoke demyelination. Therefore, we generated transgenic ASA( -/-)[ tg/ASA( -/-)] mice overexpressing the sulfatide- synthesizing enzyme galactose-3-O-sulfotransferase-1 in myelinating cells. Indeed, these tg/ ASA( -/-) mice displayed a significant increase in sulfatide storage in brain and peripheral nerves. Mice older than 1 year developed severe neurological symptoms. Nerve conduction velocity was significantly reduced in tg/ ASA(-/-) mice because of a peripheral neuropathy characterized by hypomyelinated and demyelinated axons. Inhomogeneous myelin thickness in the corpus callosum, increased frequency of hypomyelinated and demyelinated axons in corpus callosum and optic nerve, and substantially reduced myelin basic protein levels are in accordance with loss of myelin in the CNS. Thus, increasing sulfatide storage in ASA(-/-) mice leads to neurological symptoms and morphological alterations that are reminiscent of human MLD. The approach described here may also be applicable to improve other mouse models of lysosomal as well as nonlysosomal disorders.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available