myelin-basic-protein and Leukodystrophy--Metachromatic

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.

Topics: Age Factors; Animals; Cerebroside-Sulfatase; Demyelinating Diseases; Disease Models, Animal; Electromyography; Hindlimb Suspension; Humans; Leukodystrophy, Metachromatic; Lipids; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Motor Activity; Myelin Basic Protein; Myelin Sheath; Neural Conduction; Peripheral Nerves; Rotarod Performance Test; Sciatic Nerve; Spinal Cord; Sulfoglycosphingolipids

This work describes the first successful oligodendrocyte-based cell therapy for presymptomatic arylsulfatase A (ARSA) null neonate mice, a murine model for human metachromatic leukodystrophy (MLD). We found that oligodendrocyte progenitors (OLPs) engrafted and survived into adulthood when transplanted in the neonatal MLD brain. Transplanted cells integrated nondisruptively, did not produce tumors, and survived as proteolipid protein- and MBP-positive postmitotic myelinating oligodendrocytes (OLs) intermingled with endogenous MLD OLs within the adult MLD white matter. Transplanted MLD mice had reduced sulfatide accumulation in the CNS, increased brain ARSA activity, and full prevention of the electrophysiological and motor deficits that characterize untreated MLD mice. Our results provide direct evidence that healthy OLPs can tolerate the neurotoxic accumulation of sulfatides that evolves during the postnatal development of the MLD brain and contribute to OL cell replacement to limit the accumulation of sulfatides and the evolution of CNS defects in this lysosomal storage disease mouse model.

Topics: Animals; Animals, Newborn; Brain Tissue Transplantation; Cell Differentiation; Cell Movement; Cells, Cultured; Cerebroside-Sulfatase; Disease Models, Animal; Graft Survival; Leukodystrophy, Metachromatic; Mice; Mice, Knockout; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin Sheath; Nerve Fibers, Myelinated; Oligodendroglia; Stem Cell Transplantation; Sulfoglycosphingolipids; Treatment Outcome

One case of each of the following human leukodystrophies was examined immunocytochemically with antisera against myelin basic protein (MBP), myelin associated glycoprotein (MAG) and gliofibrillary acidic protein (GFA): Metachromatic leukodystrophy (MLD), connatal adrenoleukodystrophy (ALD), sudanophilic leukodystrophy of the adult (SLD) and connatal Pelizaeus-Merzbacher disease (PMD). A case of canine globoid cell leukodystrophy (GLD) was also included under the assumption that this disease was the same in the dog as in man. It was shown that the storage process in MLD and GLD did not involve MBP or MAG and that the breakdown of myelin with the formation of fat granule cells containing droplets of neutral fat in ALD and SLS proceeds in a similar way as in experimental Wallerian degeneration. In PMD, MBP is present in the vicinity of axons not surrounded by a myelin sheath demonstrable with conventional means. The globoid cells of GLD could be demonstrated to be of non-astrocytic origin.

Topics: Adolescent; Adrenoleukodystrophy; Animals; Child, Preschool; Diffuse Cerebral Sclerosis of Schilder; Dogs; Female; Glial Fibrillary Acidic Protein; Humans; Intermediate Filament Proteins; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Male; Middle Aged; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein

Topics: Central Nervous System; Glycoproteins; Humans; Immunoenzyme Techniques; Leukodystrophy, Metachromatic; Multiple Sclerosis; Myelin Basic Protein