Alterations of myelin-specific proteins and sphingolipids characterize the brains of acid sphingomyelinase-deficient mice, an animal model of niemannpick disease type A

Niemann-Pick disease type A (NPD-A) is a neurodegenerative disorder caused by sphingomyelin (SM) accumulation in lysosomes relying on reduced or absent acid sphingomyelinase activity (ASM). NPD-A patients develop progressive neurodegeneration including cerebral and cerebellar atrophy, relevant Purkinje cell and myelin deficiency with death within three years. ASM “knockout” (ASMKO) mice, an animal model of NPD-A, develop a phenotype largely mimicking that of NPD-A. The mechanisms underlying myelin formation are poorly documented in ASMKO mice. In this study we determined the content of four myelin-specific proteins, MBP, CNP, MAG and PLP, and that of myelin-enriched sphingolipids in the brains of ASMKO and wild-type mice in early stages of post-natal (pn) life. Protein and mRNA analysis revealed that in ASMKO mice beginning from 4 post natal-weeks (wk-pn), expression levels of MAG, CNP and MBP were below those observed in wild-type mice and the same applied to PLP at 10 wk-pn. Moreover, at 4 wk-pn the expression of SOX10, one of the transcription factors involved in oligodendrocyte development and maintenance, was lower in AMSKO mice. Lipid analysis showed that SM and the gangliosides GM3 and GM2 accumulated in the brains of AMSKO mice, as opposed to galactocerebroside and galactosulfocerebroside that, in parallel with the mRNAs of UGT8 and GAL3ST1, the two transferases involved in their synthesis, decreased. Myelin lipid analysis showed a progressive sphingomyelin accumulation in ASMKO mice; noteworthy, of the two sphingomyelin species known to be resolved by TLC, only that with the lower Rf accumulated. Immunohistochemical analysis showed that the reduced expression of myelin specific proteins in ASMKO mice at 4 wk-pn was not restricted to the Purkinje layer of the cerebellar cortex but involved the cerebral cortex as well. In conclusion, reduced oligodendrocyte metabolic activity is likely to be the chief cause of myelin deficiency in AMSKO mice, thus shedding light on the molecular dysfunctions underlying neurodegeneration in NPD-A.