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Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase.

Henriques A, Croixmarie V, Priestman DA, Rosenbohm A, Dirrig-Grosch S, D'Ambra E, Huebecker M, Hussain G, Boursier-Neyret C, Echaniz-Laguna A, Ludolph AC, Platt FM, Walther B, Spedding M, Loeffler JP, Gonzalez De Aguilar JL - Hum. Mol. Genet. (2015)

Bottom Line: Significant changes in lipid expression were evident in spinal cord and skeletal muscle before overt neuropathology.In silico analysis also revealed appreciable changes in sphingolipids including ceramides and glucosylceramides (GlcCer).HPLC analysis showed increased amounts of GlcCer and downstream glycosphingolipids (GSLs) in SOD1(G86R) muscle compared with wild-type littermates.

View Article: PubMed Central - PubMed

Affiliation: Université de Strasbourg, UMR_S 1118, Strasbourg, France, INSERM, U1118, Mécanismes Centraux et Péripheriques de la Neurodégénérescence, Strasbourg, France.

No MeSH data available.


Related in: MedlinePlus

Major changes in three lipid families in spinal cord and muscle of SOD1(G86R) mice. Distribution of differentially regulated phospholipid (PL), sphingolipid (SL) and triglyceride (TG) species in spinal cord (A) and muscle (B) of pre-symptomatic (PRE, light-colored bars, n = 9) and symptomatic (DIS, dark-colored bars, n = 9) SOD1(G86R) mice compared with WT littermates. Up- or down-regulated metabolites in each tissue are indicated in upper and lower panels, respectively.
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DDV439F2: Major changes in three lipid families in spinal cord and muscle of SOD1(G86R) mice. Distribution of differentially regulated phospholipid (PL), sphingolipid (SL) and triglyceride (TG) species in spinal cord (A) and muscle (B) of pre-symptomatic (PRE, light-colored bars, n = 9) and symptomatic (DIS, dark-colored bars, n = 9) SOD1(G86R) mice compared with WT littermates. Up- or down-regulated metabolites in each tissue are indicated in upper and lower panels, respectively.

Mentions: To further investigate the changes in the lipidome of SOD1(G86R) mice, we attributed hypothesis-based identifications to the significantly deregulated lipid species, according to their atomic masses in the HMDB database (29). Major changes in three lipid families were evident in the SOD1(G86R) lipidome (Fig. 2 and Supplementary Material, Fig. S3). Levels of most phospholipids and sphingolipids were decreased in spinal cord of pre-symptomatic and symptomatic mice compared with WT littermates. In contrast, levels of many of these lipids were increased in muscle at both stages. The majority of triglyceride species were reduced in muscle and, to a lesser extent, spinal cord of symptomatic mice compared with WT littermates, some even being entirely depleted. Triglycerides were also markedly depleted in plasma samples in these mice (data not shown), indicating the considerable lipid mobilization during the course of the disease (10). We obtained comparable patterns of expression when we used the METLIN database for the identification of metabolites (30) (Supplementary Material, Fig. S4). Next, we analyzed our data with ConsensusPathDB to decipher metabolic pathways of potential interest (31). This analysis revealed that changes in sphingolipid metabolism showed the highest statistical significance in the set of differentially regulated lipids in spinal cord (Supplementary Material, Table S1) and muscle (Supplementary Material, Table S2) of SOD1(G86R) mice. Several specific metabolites in this pathway appeared dysregulated: ceramide, dihydroceramide, dihydrosphingosine-1-phosphate, GlcCer, sphingomyelin and sphingosine (Supplementary Material, Fig. S5).Figure 2.


Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase.

Henriques A, Croixmarie V, Priestman DA, Rosenbohm A, Dirrig-Grosch S, D'Ambra E, Huebecker M, Hussain G, Boursier-Neyret C, Echaniz-Laguna A, Ludolph AC, Platt FM, Walther B, Spedding M, Loeffler JP, Gonzalez De Aguilar JL - Hum. Mol. Genet. (2015)

Major changes in three lipid families in spinal cord and muscle of SOD1(G86R) mice. Distribution of differentially regulated phospholipid (PL), sphingolipid (SL) and triglyceride (TG) species in spinal cord (A) and muscle (B) of pre-symptomatic (PRE, light-colored bars, n = 9) and symptomatic (DIS, dark-colored bars, n = 9) SOD1(G86R) mice compared with WT littermates. Up- or down-regulated metabolites in each tissue are indicated in upper and lower panels, respectively.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664174&req=5

DDV439F2: Major changes in three lipid families in spinal cord and muscle of SOD1(G86R) mice. Distribution of differentially regulated phospholipid (PL), sphingolipid (SL) and triglyceride (TG) species in spinal cord (A) and muscle (B) of pre-symptomatic (PRE, light-colored bars, n = 9) and symptomatic (DIS, dark-colored bars, n = 9) SOD1(G86R) mice compared with WT littermates. Up- or down-regulated metabolites in each tissue are indicated in upper and lower panels, respectively.
Mentions: To further investigate the changes in the lipidome of SOD1(G86R) mice, we attributed hypothesis-based identifications to the significantly deregulated lipid species, according to their atomic masses in the HMDB database (29). Major changes in three lipid families were evident in the SOD1(G86R) lipidome (Fig. 2 and Supplementary Material, Fig. S3). Levels of most phospholipids and sphingolipids were decreased in spinal cord of pre-symptomatic and symptomatic mice compared with WT littermates. In contrast, levels of many of these lipids were increased in muscle at both stages. The majority of triglyceride species were reduced in muscle and, to a lesser extent, spinal cord of symptomatic mice compared with WT littermates, some even being entirely depleted. Triglycerides were also markedly depleted in plasma samples in these mice (data not shown), indicating the considerable lipid mobilization during the course of the disease (10). We obtained comparable patterns of expression when we used the METLIN database for the identification of metabolites (30) (Supplementary Material, Fig. S4). Next, we analyzed our data with ConsensusPathDB to decipher metabolic pathways of potential interest (31). This analysis revealed that changes in sphingolipid metabolism showed the highest statistical significance in the set of differentially regulated lipids in spinal cord (Supplementary Material, Table S1) and muscle (Supplementary Material, Table S2) of SOD1(G86R) mice. Several specific metabolites in this pathway appeared dysregulated: ceramide, dihydroceramide, dihydrosphingosine-1-phosphate, GlcCer, sphingomyelin and sphingosine (Supplementary Material, Fig. S5).Figure 2.

Bottom Line: Significant changes in lipid expression were evident in spinal cord and skeletal muscle before overt neuropathology.In silico analysis also revealed appreciable changes in sphingolipids including ceramides and glucosylceramides (GlcCer).HPLC analysis showed increased amounts of GlcCer and downstream glycosphingolipids (GSLs) in SOD1(G86R) muscle compared with wild-type littermates.

View Article: PubMed Central - PubMed

Affiliation: Université de Strasbourg, UMR_S 1118, Strasbourg, France, INSERM, U1118, Mécanismes Centraux et Péripheriques de la Neurodégénérescence, Strasbourg, France.

No MeSH data available.


Related in: MedlinePlus