title: Increasing sulfatide synthesis in myelin-forming cells of arylsulfatase A-deficient mice causes demyelination and neurological symptoms reminiscent of human metachromatic leukodystrophy.
abstract: 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.affiliation: Institute of Physiological Chemistry, Rheinische Friedrich-Wilhelms University of Bonn, 53115 Bonn, Germany.
authors.forename: Hariharasubramanian
authors.initials: H
authors.lastname: Ramakrishnan
authors.forename: Kerstin Khalaj
authors.initials: KK
authors.lastname: Hedayati
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.forename: Carsten
authors.initials: C
authors.lastname: Wessig
authors.forename: Simon Ngamli
authors.initials: SN
authors.lastname: Fewou
authors.forename: Helena
authors.initials: H
authors.lastname: Maier
authors.forename: Hans-Hilmar
authors.initials: HH
authors.lastname: Goebel
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gieselmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Eckhardt
mesh_terms: D000367:Age Factors; D000818:Animals; D002553:Cerebroside-Sulfatase / Q000172:deficiency*; D003711:Demyelinating Diseases / Q000209:etiology*; D004195:Disease Models, Animal; D004576:Electromyography / Q000379:methods; D019417:Hindlimb Suspension / Q000379:methods; D006801:Humans; D007966:Leukodystrophy, Metachromatic / Q000150:complications / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009043:Motor Activity / Q000235:genetics; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009431:Neural Conduction / Q000502:physiology / Q000528:radiation effects; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D045442:Rotarod Performance Test; D012584:Sciatic Nerve / Q000503:physiopathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013433:Sulfoglycosphingolipids / Q000378:metabolism*
chemical_list: D008055:Lipids; D004676:Myelin Basic Protein; D013433:Sulfoglycosphingolipids; D002553:Cerebroside-Sulfatase