Sulfatide Storage in Neurons Causes Hyperexcitability and Axonal Degeneration in a Mouse Model of Metachromatic Leukodystrophy

Eckhardt, Matthias; Hedayati, Kerstin Khalaj; Pitsch, Julika; Lüllmann‐Rauch, Renate; Beck, Hiroichi; Fewou, Simon Ngamli; Gieselmann, Volkmar

doi:10.1523/jneurosci.2329-07.2007

Cited by 66 publications

(47 citation statements)

References 36 publications

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“…Metachromatic leukodystrophy patients, characterized by accumulation of sulfatide, suffer from a progressive loss of myelin and show various neurological syndromes (6). Recently, Eckhardt and colleagues showed that increasing sulfatide synthesis in a mouse model of metachromatic leukodystrophy causes demyelination and neurological syndromes (33,34). Based on these reports and our current observations, it may be possible that sulfatide-stimulated inflammatory responses in these patients and mice contribute to the disease phenotypes.…”

Section: Discussionsupporting

confidence: 65%

Sulfatide, A Major Lipid Component of Myelin Sheath, Activates Inflammatory Responses As an Endogenous Stimulator in Brain-Resident Immune Cells

Jeon

Yoon

Park

et al. 2008

The Journal of Immunology

118

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Sulfatide, a major lipid component of myelin sheath, participates in diverse cellular events of the CNS, and its cellular level has recently been implicated in many inflammation-associated neuronal diseases. Herein, we report that sulfatide alone can trigger pathological inflammatory responses in glia, brain-resident immune cells. We show that sulfatide changed the morphology of primary microglia to their activated form, and it significantly induced the production of various inflammatory mediators in primary microglia and astrocytes. Moreover, sulfatide rapidly triggered the phosphorylation of p38, ERK, and JNK within 30 min, and it markedly enhanced the NF binding activity to NF-κB and AP-1 binding elements. However, nonsulfated galactocerebroside, another major lipid component of myelin, had no effect on activation of glia. We further reveal that CD1d did not contribute to sulfatide-stimulated activation of MAPKs, although its expression was enhanced by sulfatide and sulfatide-treated microglial cells actually stimulated type II NKT cells. Sulfatide significantly stimulated the phosphorylation of MAPKs in glia from CD1d-deficient mice, and the phosphorylation levels were similar to those in wild-type littermates. Sulfatide-triggered inflammatory events appear to occur at least in part through an L-selectin-dependent mechanism. L-selectin was dramatically down-regulated upon exposure to sulfatide, and inhibition of L-selectin resulted in suppression of sulfatide-triggered responses. Collectively, these results show that abnormally released sulfatide at demyelinated regions may act as an endogenous stimulator in the brain immune system, thus causing and further exacerbating pathological conditions in the brain.

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Section: Discussionsupporting

confidence: 65%

Sulfatide, A Major Lipid Component of Myelin Sheath, Activates Inflammatory Responses As an Endogenous Stimulator in Brain-Resident Immune Cells

Jeon

Yoon

Park

et al. 2008

The Journal of Immunology

118

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“…GM2/GD2 synthase knockout, twitcher , and Sap A Ϫ / Ϫ mice exhibit degenerative changes in sciatic nerve, including myelin fragmentation and myelin layer separation with resultant synaptic rearrangement ( 118,191,274 ). GalCer or sulfatide are components of myelin GSL, and their excess accumulation causes demyelination in ASA, Krabbe disease, Sap B-defi cient patients, and mouse models ( 124 ) ( 130,275 ). In primary neuronal and neuroblastoma cultures, lysosomal accumulation of sulfatide mediates increases in endosomal ceramide that leads to apoptosis ( 276 ), thereby implicating GSL fl ux alterations due to sulfatide storage in neuronal death.…”

Section: Axonal Degenerationmentioning

confidence: 99%

Multi-system disorders of glycosphingolipid and ganglioside metabolism

Xu¹,

Barnes²,

Sun³

et al. 2010

Journal of Lipid Research

142

121

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important to a variety of cellular functions. GSLs and gangliosides are synthesized at the endoplasmic reticulum (ER) and are remodeled during transit from cis to trans Golgi by a series of glycosyl-and sialyl-transferases. These are then transported to the intracellular compartments and the plasma membrane where they become enriched in microdomains and membrane bilayers. During plasma membrane turnover, GSLs and gangliosides can be internalized and partially or completely degraded in the endosomal/lysosomal system to sphingosine and free fatty acids that are then transported or fl ipped across late endosomal and lysosomal membranes for recycling or for use as signaling molecules ( 2, 3 ). GSL metabolic pathwaysGSL biosynthesis begins with condensation of serine and palmitoyl-CoA catalyzed by serine-palmitoyltransferase (SPT) on the cytoplasmic face of the ER, leading to de novo biosynthesis of ceramide, the core of GSLs (

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“…In a mouse model of MLD, the CGT/ASA (-/-) mouse (in which ceramide galactosyltransferase (CGT) was overexpressed in an ASA (-/-) mouse), C18-sulfogalactosylceramide (SGalCer) accumulated to significant levels in neurons. These mice exhibited nerve fiber degeneration in the spinal cord, suggesting that C18-SGalCer accumulation in neurons may contribute to the disease phenotype (Eckhardt et al 2007). In a different model of MLD, a CGT transgenic mouse (which overexpresses CGT in a normal ASA background), both C18-GalCer and C18-sulfatide accumulated in neurons.…”

Section: Metachromatic Leukodystrophymentioning

confidence: 99%

The Role of the Ceramide Acyl Chain Length in Neurodegeneration: Involvement of Ceramide Synthases

2010

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Ceramide forms the backbone of all complex sphingolipids and has been the focus of considerable attention in the past few years due to the discovery that ceramide plays vital roles as an intracellular messenger. Ceramide, which consists of a sphingoid long chain base to which a fatty acid is N-acylated, is synthesized in mammals by a family of ceramide synthases (CerS), each of which uses a restricted subset of fatty acyl CoAs for N-acylation. Sphingolipids are found at high levels in nervous tissue, where they perform a variety of important functions in both the adult and the maturing brain. We now review what is known about the role of the acyl chain composition of ceramides and sphingolipids in normal brain development and in neurological diseases. Specifically, we attempt to integrate the information that is available about CerS expression and activity in the brain with the changes in the acyl chain composition of ceramide and complex sphingolipids in a number of neurodegenerative diseases and conditions, such as metachromatic leukodystrophy, neuronal ceroid lipofuscinoses, HIV infection, aging, Alzheimer's disease, ischemia, and epilepsy. We conclude that understanding the direct relationship between the CerS proteins and neurological conditions will be of great importance for delineating the precise roles of sphingolipids in the brain and is likely to be the subject of intense research activity in the years ahead.

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Sulfatide Storage in Neurons Causes Hyperexcitability and Axonal Degeneration in a Mouse Model of Metachromatic Leukodystrophy

Cited by 66 publications

References 36 publications

Sulfatide, A Major Lipid Component of Myelin Sheath, Activates Inflammatory Responses As an Endogenous Stimulator in Brain-Resident Immune Cells

Sulfatide, A Major Lipid Component of Myelin Sheath, Activates Inflammatory Responses As an Endogenous Stimulator in Brain-Resident Immune Cells

Multi-system disorders of glycosphingolipid and ganglioside metabolism

The Role of the Ceramide Acyl Chain Length in Neurodegeneration: Involvement of Ceramide Synthases

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