Phenotype of arylsulfatase A-deficient mice: Relationship to human metachromatic leukodystrophy

Abstract

Metachromatic leukodystrophy is a lysosomal sphingolipid storage disorder caused by the deficiency of arylsulfatase A. The disease is characterized by progressive demyelination, causing various neurologic symptoms. Since no naturally occurring animal model of the disease is available, we have generated arylsulfatase A-deficient mice. Deficient animals store the sphingolipid cerebroside-3-sulfate in various neuronal and nonneuronal tissues. The storage pattern is comparable to that of affected humans, but gross defects of white matter were not observed up to the age of 2 years. A reduction of axonal cross-sectional area and an astrogliosis were observed in 1-year-old mice; activation of microglia started at 1 year and was generalized at 2 years. Purkinje cell dendrites show an altered morphology. In the acoustic ganglion numbers of neurons and myelinated fibers are severely decreased, which is accompanied by a loss of brainstem auditory-evoked potentials. Neurologic examination reveals significant impairment of neuromotor coordination.

Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations

“…Untreated and mock-treated ASA-deficient mice showed a pattern of storage granules identical to that of 129/Ola x B6 outbred mice which was described previously. 2,3 Thus, storage was found in 40-100% of the bile duct profiles of liver sections obtained from mock-treated mice (n = 7) (Table 1). Consistently, a large number of granules was readily detectable in all epithelial cells of affected bile ducts (Figure 2a).…”

“…2 To determine a possible effect of gene therapy on neurons we determined cross-sectional areas of axons in the saphenus nerve, the sciatic nerve and the optic nerve around 12 months after birth (Figure 4). For all nerves the cross- …”

“…stages in the disease progression of MLD. 2,3 Analyses of these mice lent new insights into the disease pathogenesis which were compromised in humans due to the lack of appropriate premortem tissue material. Thus, the view that the sulfatide storage in oligodendroglial and Schwann cells alone accounts for the complex pathogenic disease process seems to be oversimplified.…”

“…ASA deficiency was also found to have a major impact on other cell types like astrocytes, microglial cells and subpopulations of neuronal cells, some of which show cellular malformations and dysfunctions even in the absence of histochemically detectable sulfatide storage. 2 In particular, ASA-deficient mice display a reduced diameter and cross-sectional area of central and peripheral nervous system axons. 2 The deficient mice show various progressive cerebellar deficits and a decline in brain stem auditory-evoked potentials between the age of 3 and 9 months.…”

“…2 In particular, ASA-deficient mice display a reduced diameter and cross-sectional area of central and peripheral nervous system axons. 2 The deficient mice show various progressive cerebellar deficits and a decline in brain stem auditory-evoked potentials between the age of 3 and 9 months. 4 This is due to a loss of ganglion cells in the acoustic ganglion of ASA-deficient mice.…”