RT Journal Article
SR Electronic
T1 Increasing Sulfatide Synthesis in Myelin-Forming Cells of Arylsulfatase A-Deficient Mice Causes Demyelination and Neurological Symptoms Reminiscent of Human Metachromatic Leukodystrophy
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9482
OP 9490
DO 10.1523/JNEUROSCI.2287-07.2007
VO 27
IS 35
A1 Hariharasubramanian Ramakrishnan
A1 Kerstin Khalaj Hedayati
A1 Renate Lüllmann-Rauch
A1 Carsten Wessig
A1 Simon Ngamli Fewou
A1 Helena Maier
A1 Hans-Hilmar Goebel
A1 Volkmar Gieselmann
A1 Matthias Eckhardt
YR 2007
UL http://www.jneurosci.org/content/27/35/9482.abstract
AB 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.