Loss of SPNS1, a lysosomal transporter, in the nervous system causes dysmyelination and white matter dysplasia

Protein spinster homolog 1 (SPNS1) is a lysosomal transporter of lysophospholipids and sphingosine, which has recently been identified to be mutated in patients with neurodegeneration. However, its physiological role, especially in the nervous system, remains largely unknown. In this study, we generated, for the first time, nervous system-specific Spns1 knockout mice, Spns1flox/flox;nestin-Cre, and found that the mutant mice develop neurological symptoms, such as epilepsy, and growth retardation, and die by 5 weeks of age. The mutant mice exhibited dysmyelination and oligodendrocyte shedding, while maintaining the neurons. Mutant mouse brains showed accumulation of lysophospholipids, predominantly in regions, such as the olfactory bulb and hippocampus. Furthermore, whereas sphingosine accumulated in the mutant mouse brain, the levels of ceramide and sphingoglycolipids, which are the main myelin components, were decreased. Our findings imply that abnormal sphingosine metabolism causes dysmyelination and white matter dysplasia in brain-specific Spns1-knockout mice, and indicate a possible role of SPNS1 mutation in the pathogenesis of congenital cerebral white matter dysplasia in humans.