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

Henriques, Alexandre Cruz; Huebecker, Mylene; Blasco, Hélène; Keime, Céline; Andres, Christian R.; Corcia, Philippe; Priestman, David A.; Platt, Frances M.; Spedding, Michael; Loeffler, Jean‐Philippe

doi:10.1038/s41598-017-05313-0

Cited by 43 publications

(49 citation statements)

References 92 publications

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“…These authors also observed the associated upregulation of glucosylceramide synthase in the muscle of ALS model mice and in the CSF of ALS patients. A recent study reports the analysis of some lipids in the CSF of 14 ALS patients (recruited in our ALS center but different from the patients included in this present study) confirming the increased levels of GlcCer and GM1a compared to controls, as in our present study 17 .…”

Section: Discussionsupporting

confidence: 91%

Lipidomics Reveals Cerebrospinal-Fluid Signatures of ALS

Blasco

Veyrat-Durebex

Bocca

et al. 2017

Sci Rep

117

101

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Amyotrophic lateral sclerosis (ALS), the commonest adult-onset motor neuron disorder, is characterized by a survival span of only 2–5 years after onset. Relevant biomarkers or specific metabolic signatures would provide powerful tools for the management of ALS. The main objective of this study was to investigate the cerebrospinal fluid (CSF) lipidomic signature of ALS patients by mass spectrometry to evaluate the diagnostic and predictive values of the profile. We showed that ALS patients (n = 40) displayed a highly significant specific CSF lipidomic signature compared to controls (n = 45). Phosphatidylcholine PC(36:4), higher in ALS patients (p = 0.0003) was the most discriminant molecule, and ceramides and glucosylceramides were also highly relevant. Analysis of targeted lipids in the brain cortex of ALS model mice confirmed the role of some discriminant lipids such as PC. We also obtained good models for predicting the variation of the ALSFRS-r score from the lipidome baseline, with an accuracy of 71% in an independent set of patients. Significant predictions of clinical evolution were found to be correlated to sphingomyelins and triglycerides with long-chain fatty acids. Our study, which shows extensive lipid remodelling in the CSF of ALS patients, provides a new metabolic signature of the disease and its evolution with good predictive performance.

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Section: Discussionsupporting

confidence: 91%

Lipidomics Reveals Cerebrospinal-Fluid Signatures of ALS

Blasco

Veyrat-Durebex

Bocca

et al. 2017

Sci Rep

117

101

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“…RNA-sequencing was performed as previously described (Henriques et al, 2017 ). Briefly, total RNA was extracted from frozen samples of spinal cord from 95 days old mice ( n = 5/group).…”

Section: Methodsmentioning

confidence: 99%

Sphingolipid Metabolism Is Dysregulated at Transcriptomic and Metabolic Levels in the Spinal Cord of an Animal Model of Amyotrophic Lateral Sclerosis

Henriques

Croixmarie

Bouscary

et al. 2018

Front. Mol. Neurosci.

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Lipid metabolism is drastically dysregulated in amyotrophic lateral sclerosis and impacts prognosis of patients. Animal models recapitulate alterations in the energy metabolism, including hypermetabolism and severe loss of adipose tissue. To gain insight into the molecular mechanisms underlying disease progression in amyotrophic lateral sclerosis, we have performed RNA-sequencing and lipidomic profiling in spinal cord of symptomatic SOD1G86R mice. Spinal transcriptome of SOD1G86R mice was characterized by differential expression of genes related to immune system, extracellular exosome, and lysosome. Hypothesis-driven identification of metabolites showed that lipids, including sphingomyelin(d18:0/26:1), ceramide(d18:1/22:0), and phosphatidylcholine(o-22:1/20:4) showed profound altered levels. A correlation between disease severity and gene expression or metabolite levels was found for sphingosine, ceramide(d18:1/26:0), Sgpp2, Sphk1, and Ugt8a. Joint-analysis revealed a significant enrichment of glycosphingolipid metabolism in SOD1G86R mice, due to the down-regulation of ceramide, glucosylceramide, and lactosylceramide and the overexpression of genes involved in their recycling in the lysosome. A drug-gene interaction database was interrogated to identify potential drugs able to modulate the dysregulated genes from the signaling pathway. Our results suggest that complex lipids are pivotally changed during the first phase of motor symptoms in an animal model of amyotrophic lateral sclerosis.

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“…Collectively, these findings suggest that the reductions in GBA activity that occur in SOD1 G93A mice during the disease are a part of a compensatory response to slow progression (Dodge et al, 2015 ). Indeed, enhancing low-level inhibition of GBA activity in SOD1 G93A mice preserved the integrity of their motor units (Henriques et al, 2017 ). CMT is the most common hereditary neuromuscular disorder, with an estimated prevalence of 40 cases per 100,000 individuals (Martyn and Hughes, 1997 ).…”

Section: Gaucher Disease Glucocerebrosidase and Glucosylceramidementioning

confidence: 99%

Lipid Involvement in Neurodegenerative Diseases of the Motor System: Insights from Lysosomal Storage Diseases

Dodge

2017

Front. Mol. Neurosci.

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Lysosomal storage diseases (LSDs) are a heterogeneous group of rare inherited metabolic diseases that are frequently triggered by the accumulation of lipids inside organelles of the endosomal-autophagic-lysosomal system (EALS). There is now a growing realization that disrupted lysosomal homeostasis (i.e., lysosomal cacostasis) also contributes to more common neurodegenerative disorders such as Parkinson disease (PD). Lipid deposition within the EALS may also participate in the pathogenesis of some additional neurodegenerative diseases of the motor system. Here, I will highlight the lipid abnormalities and clinical manifestations that are common to LSDs and several diseases of the motor system, including amyotrophic lateral sclerosis (ALS), atypical forms of spinal muscular atrophy, Charcot–Marie–Tooth disease (CMT), hereditary spastic paraplegia (HSP), multiple system atrophy (MSA), PD and spinocerebellar ataxia (SCA). Elucidating the underlying basis of intracellular lipid mislocalization as well as its consequences in each of these disorders will likely provide innovative targets for therapeutic research.

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

Cited by 43 publications

References 92 publications

Lipidomics Reveals Cerebrospinal-Fluid Signatures of ALS

Lipidomics Reveals Cerebrospinal-Fluid Signatures of ALS

Sphingolipid Metabolism Is Dysregulated at Transcriptomic and Metabolic Levels in the Spinal Cord of an Animal Model of Amyotrophic Lateral Sclerosis

Lipid Involvement in Neurodegenerative Diseases of the Motor System: Insights from Lysosomal Storage Diseases

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