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Alterations of myelin‐specific proteins and sphingolipids characterize the brains of acid sphingomyelinase‐deficient mice, an animal model of Niemann–Pick disease type A
Author(s) -
Buccinnà Barbara,
Piccinini Marco,
Prinetti Alessandro,
Scandroglio Federica,
Prioni Simona,
Valsecchi Manuela,
Votta Barbara,
Grifoni Silvia,
Lupino Elisa,
Ramondetti Cristina,
Schuchman Edward H.,
Giordana Maria Teresa,
Sonnino Sandro,
Rinaudo Maria Teresa
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.05947.x
Subject(s) - myelin , sphingolipid , sphingomyelin , niemann–pick disease , proteolipid protein 1 , biology , sphingomyelin phosphodiesterase , oligodendrocyte , acid sphingomyelinase , ceramide , npc1 , niemann–pick disease, type c , galactocerebroside , biochemistry , myelin basic protein , endocrinology , medicine , central nervous system , cell , cholesterol , apoptosis , endosome
Niemann–Pick disease (NPD) type A is a neurodegenerative disorder caused by sphingomyelin (SM) accumulation in lysosomes relying on reduced or absent acid sphingomyelinase (ASM) activity. NPD‐A patients develop progressive neurodegeneration including cerebral and cerebellar atrophy, relevant Purkinje cell and myelin deficiency with death within 3 years. ASM ‘knock‐out’ (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, myelin basic protein (MBP), 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase (CNP), myelin associated glycoprotein (MAG) and proteolipid protein (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), the 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 ASMKO mice. Lipid analysis showed that SM and the gangliosides GM3 and GM2 accumulated in the brains of ASMKO mice, as opposed to galactocerebroside and galactosulfocerebroside that, in parallel with the mRNAs of UDP‐galactose ceramide galactosyltransferase and galactose‐3‐O‐sulfotransferase 1, 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. The immunohistochemical analysis showed that the reduced expression of myelin specific proteins in ASMKO mice at 10 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 ASMKO mice, thus shedding light on the molecular dysfunctions underlying neurodegeneration in NPD‐A.