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

Henriques, Alexandre Cruz; Croixmarie, Vincent; Priestman, David A.; Rosenbohm, Angela; Dirrig‐Grosch, Sylvie; D’Ambra, Eleonora; Huebecker, Mylene; Hussain, Ghulam; Boursier-Neyret, Claire; Echaniz‐Laguna, Andoni; Ludolph, Albert C.; Platt, Frances M.; Walther, Bernard; Spedding, Michael; Loeffler, Jean‐Philippe; Aguilar, José-Luis González de

doi:10.1093/hmg/ddv439

Cited by 82 publications

(94 citation statements)

References 64 publications

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“…Alterations in sphingolipids have been associated with a wide variety of neurodegenerative diseases. Several sphingolipids serve as bioactive signaling molecules in a plethora of pathways and have been implicated in Alzheimer's (48,49), Parkinson's (50), and ALS (51). We sought to determine if changes in sphingolipid metabolism may mediate CMT phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Decreased ceramide underlies mitochondrial dysfunction in Charcot‐Marie‐Tooth 2F

et al. 2018

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Charcot-Marie-Tooth (CMT) disease is the most commonly inherited neurologic disorder, but its molecular mechanisms remain unclear. One variant of CMT, 2F, is characterized by mutations in heat shock protein 27 (Hsp27). As bioactive sphingolipids have been implicated in neurodegenerative diseases, we sought to determine if their dysregulation is involved in CMT. Here, we show that Hsp27 knockout mice demonstrated decreases in ceramide in peripheral nerve tissue and that the disease-associated Hsp27 S135F mutant demonstrated decreases in mitochondrial ceramide. Given that Hsp27 is a chaperone protein, we examined its role in regulating ceramide synthases (CerSs), an enzyme family responsible for catalyzing generation of the sphingolipid ceramide. We determined that CerSs colocalized with Hsp27, and upon the presence of S135F mutants, CerS1 lost its colocalization with mitochondria suggesting that decreased mitochondrial ceramides result from reduced mitochondrial CerS localization rather than decreased CerS activity. Mitochondria in mutant cells appeared larger with increased interconnectivity. Furthermore, mutant cell lines demonstrated decreased mitochondrial respiratory function and increased autophagic flux. Mitochondrial structural and functional changes were recapitulated by blocking ceramide generation pharmacologically. These results suggest that mutant Hsp27 decreases mitochondrial ceramide levels, producing structural and functional changes in mitochondria leading to neuronal degeneration.-Schwartz, N. U., Linzer, R. W., Truman, J.-P., Gurevich, M., Hannun, Y. A., Senkal, C. E., Obeid, L. M. Decreased ceramide underlies mitochondrial dysfunction in Charcot-Marie-Tooth 2F.

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Section: Discussionmentioning

confidence: 99%

Decreased ceramide underlies mitochondrial dysfunction in Charcot‐Marie‐Tooth 2F

et al. 2018

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“…GlcCer and downstream gangliosides were analysed as described previously 13 . Tissues were homogenized in water using an Ultraturax T25 probe homogenizer (IKA, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, inhibition of GlcCer synthesis caused impaired nerve regeneration after peripheral nerve injury and was highly deleterious in SOD1 G86R mice 13, 14 . The expression of ugcg , a gene encoding the enzyme catalysing the first step of glycosphingolipid synthesis, was strongly upregulated in muscle biopsies of ALS patients, independent of disease severity, suggesting a dysregulation in glycosphingolipid homeostasis in ALS at early disease stage.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis

Henriques

Huebecker

Blasco

et al. 2017

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Recent metabolomic reports connect dysregulation of glycosphingolipids, particularly ceramide and glucosylceramide, to neurodegeneration and to motor unit dismantling in amyotrophic lateral sclerosis at late disease stage. We report here altered levels of gangliosides in the cerebrospinal fluid of amyotrophic lateral sclerosis patients in early disease stage. Conduritol B epoxide is an inhibitor of acid beta-glucosidase, and lowers glucosylceramide degradation. Glucosylceramide is the precursor for all of the more complex glycosphingolipids. In SOD1G86R mice, an animal model of amyotrophic lateral sclerosis, conduritol B epoxide preserved ganglioside distribution at the neuromuscular junction, delayed disease onset, improved motor function and preserved motor neurons as well as neuromuscular junctions from degeneration. Conduritol B epoxide mitigated gene dysregulation in the spinal cord and restored the expression of genes involved in signal transduction and axonal elongation. Inhibition of acid beta-glucosidase promoted faster axonal elongation in an in vitro model of neuromuscular junctions and hastened recovery after peripheral nerve injury in wild type mice. Here, we provide evidence that glycosphingolipids play an important role in muscle innervation, which degenerates in amyotrophic lateral sclerosis from the early disease stage. This is a first proof of concept study showing that modulating the catabolism of glucosylceramide may be a therapeutic target for this devastating disease.

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“…However, there was an enrichment of glucosphingolipid metabolism in Tg-SOD1 G86R mice (Henriques et al, 2018). Another study confirmed the downregulation of sphingolipids and the upregulation of glucosylceramides (Henriques et al, 2015). In the blood of Tg-SOD1 G93A mice, the concentration of 12-hydroxyeicosatetranoic acid (12-HETE), a derivative of the lipoxygenase pathway, has been found to be increased, when the symptoms of ALS appear (Trostchansky et al, 2016).…”

Section: Lipidomicsmentioning

confidence: 86%

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

et al. 2019

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Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder. Two forms are recognized, familial (FALS) that accounts for 5–10% of ALS cases, and sporadic (SALS) that accounts for the rest. Early diagnosis of ALS is important because it improves their therapeutic efficacy. Current diagnosis is based on clinical assessment and requires approximately 12 months, leading to a significant delay in drug administration. Therefore, new methods are required for the earlier diagnosis of ALS. Screening for pathogenic variants in known ALS‐associated genes is already exploited as a diagnostic tool in ALS but cannot be applied for population‐based screening. New circulating biomarkers (proteins or small molecules) are needed for initial screening, whereas specific diagnostic methods can be applied to confirm the presence of pathogenic variants in the selected population subgroup. Lipids appear as promising biomarkers for population‐based screening and for monitoring disease progression. Genetic analysis can also assist in the prediction of disease progression by analyzing disease‐modifying genes, for example, EPHA4 and CHGB. Furthermore, molecular diagnosis will aid the stratification of ALS patients for improved pharmacological approaches. Here, we discuss current and novel diagnostic strategies and how they can be applied to revolutionize the field of ALS molecular diagnosis.

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

Cited by 82 publications

References 64 publications

Decreased ceramide underlies mitochondrial dysfunction in Charcot‐Marie‐Tooth 2F

Decreased ceramide underlies mitochondrial dysfunction in Charcot‐Marie‐Tooth 2F

Inhibition of β-Glucocerebrosidase Activity Preserves Motor Unit Integrity in a Mouse Model of Amyotrophic Lateral Sclerosis

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

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