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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

UGCG expression in human ALS muscle. (A) Relative GCS mRNA levels in deltoid muscle of 8 ALS patients and 12 control subjects. *P < 0.05. (B) Representative photomicrographs showing GCS immunostaining on cross-sections of vastus lateralis muscle of control (left panels) and ALS (right panels) individuals. Lower panels are magnifications of upper insets. Immunoreactive inclusions are indicated by arrow heads. Scale bar, 50 µm. Cross-sectional area of fibers (C), and distribution of fiber diameters (D) in sections as in B. Measurements were performed on 579 and 245 fibers from 4 control subjects and 6 ALS patients, respectively. ***P < 0.001. (E) Representative photomicrographs showing immunoperoxidase staining of GCS (left panels) and TDP-43 (right panels) on adjacent cross-sections of vastus lateralis muscle in ALS patients. Lower panels are magnifications of upper insets. Immunoreactive inclusions are indicated by arrow heads. Scale bars, 100 µm in upper panels, and 200 µm in lower panels.
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DDV439F4: UGCG expression in human ALS muscle. (A) Relative GCS mRNA levels in deltoid muscle of 8 ALS patients and 12 control subjects. *P < 0.05. (B) Representative photomicrographs showing GCS immunostaining on cross-sections of vastus lateralis muscle of control (left panels) and ALS (right panels) individuals. Lower panels are magnifications of upper insets. Immunoreactive inclusions are indicated by arrow heads. Scale bar, 50 µm. Cross-sectional area of fibers (C), and distribution of fiber diameters (D) in sections as in B. Measurements were performed on 579 and 245 fibers from 4 control subjects and 6 ALS patients, respectively. ***P < 0.001. (E) Representative photomicrographs showing immunoperoxidase staining of GCS (left panels) and TDP-43 (right panels) on adjacent cross-sections of vastus lateralis muscle in ALS patients. Lower panels are magnifications of upper insets. Immunoreactive inclusions are indicated by arrow heads. Scale bars, 100 µm in upper panels, and 200 µm in lower panels.

Mentions: Increased expression of GCS was also apparent in muscle of ALS patients compared with that of control subjects (Fig. 4A). This was confirmed by histological analysis of human muscle biopsies (Table 2). GCS appeared in the form of highly immunoreactive cytoplasmic inclusions usually located in the center of myofibers (Fig. 4B). These inclusions were more frequent in fibers with reduced cross-sectional area and, in many cases, with denervation-induced angulated morphology (Fig. 4C and D). Such a pattern of protein aggregation prompted us to investigate Tar-DNA binding protein-43 (TDP-43), because its abnormal accumulation in cytoplasmic inclusions is a pathological hallmark seen in the central nervous system in patients with frontotemporal lobar degeneration and ALS as well as in the muscles of patients with sporadic inclusion body myositis and its rare hereditary form presenting with Paget's disease of the bone and frontotemporal dementia (37–39). We showed that GCS co-localized with TDP-43 within the same inclusions in affected myofibers (Fig. 4E), which extends TDP-43 proteinopathy to ALS muscle and reveals GCS to be a major component of the inclusions that characterize human ALS muscle pathology.Table 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)

UGCG expression in human ALS muscle. (A) Relative GCS mRNA levels in deltoid muscle of 8 ALS patients and 12 control subjects. *P < 0.05. (B) Representative photomicrographs showing GCS immunostaining on cross-sections of vastus lateralis muscle of control (left panels) and ALS (right panels) individuals. Lower panels are magnifications of upper insets. Immunoreactive inclusions are indicated by arrow heads. Scale bar, 50 µm. Cross-sectional area of fibers (C), and distribution of fiber diameters (D) in sections as in B. Measurements were performed on 579 and 245 fibers from 4 control subjects and 6 ALS patients, respectively. ***P < 0.001. (E) Representative photomicrographs showing immunoperoxidase staining of GCS (left panels) and TDP-43 (right panels) on adjacent cross-sections of vastus lateralis muscle in ALS patients. Lower panels are magnifications of upper insets. Immunoreactive inclusions are indicated by arrow heads. Scale bars, 100 µm in upper panels, and 200 µm in lower panels.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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DDV439F4: UGCG expression in human ALS muscle. (A) Relative GCS mRNA levels in deltoid muscle of 8 ALS patients and 12 control subjects. *P < 0.05. (B) Representative photomicrographs showing GCS immunostaining on cross-sections of vastus lateralis muscle of control (left panels) and ALS (right panels) individuals. Lower panels are magnifications of upper insets. Immunoreactive inclusions are indicated by arrow heads. Scale bar, 50 µm. Cross-sectional area of fibers (C), and distribution of fiber diameters (D) in sections as in B. Measurements were performed on 579 and 245 fibers from 4 control subjects and 6 ALS patients, respectively. ***P < 0.001. (E) Representative photomicrographs showing immunoperoxidase staining of GCS (left panels) and TDP-43 (right panels) on adjacent cross-sections of vastus lateralis muscle in ALS patients. Lower panels are magnifications of upper insets. Immunoreactive inclusions are indicated by arrow heads. Scale bars, 100 µm in upper panels, and 200 µm in lower panels.
Mentions: Increased expression of GCS was also apparent in muscle of ALS patients compared with that of control subjects (Fig. 4A). This was confirmed by histological analysis of human muscle biopsies (Table 2). GCS appeared in the form of highly immunoreactive cytoplasmic inclusions usually located in the center of myofibers (Fig. 4B). These inclusions were more frequent in fibers with reduced cross-sectional area and, in many cases, with denervation-induced angulated morphology (Fig. 4C and D). Such a pattern of protein aggregation prompted us to investigate Tar-DNA binding protein-43 (TDP-43), because its abnormal accumulation in cytoplasmic inclusions is a pathological hallmark seen in the central nervous system in patients with frontotemporal lobar degeneration and ALS as well as in the muscles of patients with sporadic inclusion body myositis and its rare hereditary form presenting with Paget's disease of the bone and frontotemporal dementia (37–39). We showed that GCS co-localized with TDP-43 within the same inclusions in affected myofibers (Fig. 4E), which extends TDP-43 proteinopathy to ALS muscle and reveals GCS to be a major component of the inclusions that characterize human ALS muscle pathology.Table 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