Proteomics of the corpus callosum to identify novel factors involved in hypomyelinated Niemann-Pick Type C disease mice

Yang, Fan; Guan, Yudong; Feng, Xiao; Rolfs, Arndt; Schlüter, Hartmut; Luo, Jiankai

doi:10.1186/s13041-019-0440-9

Cited by 23 publications

(21 citation statements)

References 67 publications

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“…But, in Figure 2, the C26 ceramides are relatively normal, so this anomaly might be well compensated. Decreased CERS2 protein levels were also reported for the hypomyelination pathology in Niemann–Pick type C disease [146], and, interestingly, they were observed to precede tau pathology at a preclinical stage of Alzheimer’s disease [111]. The reduction of CERS1 protein in the Atxn2 -CAG100-KIN mouse was accompanied by a decrease of Cers1 mRNA and correlated with the mild deficiency of many ceramide species.…”

Section: Discussionmentioning

confidence: 75%

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Sen

Arsovic

Meierhofer

et al. 2019

IJMS

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Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2) with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-Knockin (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin, and gangliosides GM1a/GD1b despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide–sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage and not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals; thus, our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode, and mouse orthologs as mTORC1 inhibitors and autophagy promoters.

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Section: Discussionmentioning

confidence: 75%

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Sen

Arsovic

Meierhofer

et al. 2019

IJMS

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“…CERS2 inactivity appears pathogenic in view of the cellular effort to upregulate Cers2 transcripts; it would reduce the levels of very-long-chain ceramides in mature oligodendroglia, but in Figure 2 the C26 ceramides are relatively normal, so this anomaly might be well compensated. Decreased CERS2 protein levels were also reported for the hypomyelination pathology in Niemann-Pick type C disease [141], and interestingly they were observed to precede tau pathology at a preclinical stage of Alzheimer's disease [106]. The reduction of CERS1 protein in the Atxn2-CAG100-KIN mouse was accompanied by a decrease of Cers1 mRNA and correlated with the mild deficiency of many ceramide species.…”

Section: Discussionmentioning

confidence: 67%

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Sen¹,

Arsovic²,

Meierhofer³

et al. 2019

Preprint

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Ataxin-2 (ATXN2) acts during stress-responses, modulating mRNA translation and nutrient metabolism. Atxn2 knockout mice exhibit progressive obesity, dyslipidemia and insulin resistance. Conversely, the progressive ATXN2 gain-of-function due to polyGlutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2), with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-KnockIn (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin and gangliosides GM1a/GD1b, despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides, with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, of Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very-long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage, not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals, so our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode and mouse orthologs as mTORC1 inhibitors and autophagy promoters.

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“…Intracellular ganglioside stores and neuronal degeneration were shown in large pyramidal and Purkinje cells, and in neurons of the thalamus and the hippocampus [ 39 , 109 , 112 , 113 ]. In particular, hypomyelination was conspicuous in the cerebral white matter and corpus callosum of NPC1 −/− mice and surely is one basis for their lower brain weight [ 114 , 115 , 116 , 117 , 118 ]. In NPC1 −/− mice, from early postnatal development onwards, defects of differentiation of post-mitotic premyelinating oligodendrocytes into mature myelinating oligodendrocytes have been described by various groups [ 114 , 117 , 118 ].…”

Section: Discussionmentioning

confidence: 99%

“…In particular, hypomyelination was conspicuous in the cerebral white matter and corpus callosum of NPC1 −/− mice and surely is one basis for their lower brain weight [ 114 , 115 , 116 , 117 , 118 ]. In NPC1 −/− mice, from early postnatal development onwards, defects of differentiation of post-mitotic premyelinating oligodendrocytes into mature myelinating oligodendrocytes have been described by various groups [ 114 , 117 , 118 ]. However, the amount of demyelinization varies between different parts of the brain [ 119 , 120 , 121 ].…”

Section: Discussionmentioning

confidence: 99%

Gender-Specific Effects of Two Treatment Strategies in a Mouse Model of Niemann-Pick Disease Type C1

Holzmann

Witt

Rolfs

et al. 2021

IJMS

Self Cite

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In a mouse model of Niemann-Pick disease type C1 (NPC1), a combination therapy (COMBI) of miglustat (MIGLU), the neurosteroid allopregnanolone (ALLO) and the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HPßCD) has previously resulted in, among other things, significantly improved motor function. The present study was designed to compare the therapeutic effects of the COMBI therapy with that of MIGLU or HPßCD alone on body and brain weight and the behavior of NPC1−/− mice in a larger cohort, with special reference to gender differences. A total of 117 NPC1−/− and 123 NPC1+/+ mice underwent either COMBI, MIGLU only, HPßCD only, or vehicle treatment (Sham), or received no treatment at all (None). In male and female NPC1−/− mice, all treatments led to decreased loss of body weight and, partly, brain weight. Concerning motor coordination, as revealed by the accelerod test, male NPC1−/− mice benefited from COMBI treatment, whereas female mice benefited from COMBI, MIGLU, and HPßCD treatment. As seen in the open field test, the reduced locomotor activity of male and female NPC1−/− mice was not significantly ameliorated in either treatment group. Our results suggest that in NPC1−/− mice, each drug treatment scheme had a beneficial effect on at least some of the parameters evaluated compared with Sham-treated mice. Only in COMBI-treated male and female NPC+/+ mice were drug effects seen in reduced body and brain weights. Upon COMBI treatment, the increased dosage of drugs necessary for anesthesia in Sham-treated male and female NPC1−/− mice was almost completely reduced only in the female groups.

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Proteomics of the corpus callosum to identify novel factors involved in hypomyelinated Niemann-Pick Type C disease mice

Cited by 23 publications

References 67 publications

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Gender-Specific Effects of Two Treatment Strategies in a Mouse Model of Niemann-Pick Disease Type C1

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