Lipidomics Reveals Cerebrospinal-Fluid Signatures of ALS

Blasco, Hélène; Veyrat-Durebex, Charlotte; Bocca, Cinzia; Patin, Franck; Vourc’h, Patrick; Nzoughet, Judith Kouassi; Lenaers, Guy; Andres, Christian R.; Simard, Gilles; Corcia, Philippe; Reynier, Pascal

doi:10.1038/s41598-017-17389-9

Cited by 120 publications

(119 citation statements)

References 32 publications

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“…The lipid profiling efforts in a SCA2 patient cerebellum and in spinocerebellar tissues from an authentic SCA2 mouse model showed deficits for very-long-chain C24 sphingomyelin as the main consistent finding in both organisms. A reduction of very-long-chain sphingomyelin was also observed in the CSF and blood of ALS patients, and this deficit correlated with lowest survival [128,129]. C24 sphingomyelin interacts with cholesterol in lipid bilayers, as important stabilizing elements for the plasma membrane particularly in myelinating glia cells [130,131].…”

Section: Discussionmentioning

confidence: 96%

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Sen¹,

Arsovic²,

Meierhofer³

et al. 2019

Preprint

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Ataxin-2 (ATXN2) acts during stress-responses, modulating mRNA translation and nutrient metabolism. Atxn2 knockout mice exhibit progressive obesity, dyslipidemia and insulin resistance. Conversely, the progressive ATXN2 gain-of-function due to polyGlutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2), with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-KnockIn (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin and gangliosides GM1a/GD1b, despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides, with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, of Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very-long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage, not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals, so our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode and mouse orthologs as mTORC1 inhibitors and autophagy promoters.

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Section: Discussionmentioning

confidence: 96%

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Sen¹,

Arsovic²,

Meierhofer³

et al. 2019

Preprint

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“…Our observation concerning the drop in ν as N (CH 3 ) [19], assigned to choline group-component of the phosphatidylcholine and sphingomyelin, in ALS astrocytes together with the new analysis of the region around 1465 and 1377 cm −1 [40] (Figure 4D), point to a direct influence of these groups in lipid homeostasis in ALS astrocytes. Blasco and coworkers [51] highlighted phosphatidylcholine as a possible marker in the cerebrospinal fluid of ALS patients. For normal plasma membrane functionality and fluidity, lipid domains known as lipid rafts (mostly composed of sphingolipids and cholesterol) are crucial.…”

Section: F I G U R Ementioning

confidence: 99%

Lipids status and copper in a single astrocyte of the rat model for amyotrophic lateral sclerosis: Correlative synchrotron‐based X‐ray and infrared imaging

Kreuzer

Stamenković

Chen

et al. 2020

Journal of Biophotonics

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, causing death of motor neurons controlling voluntary muscles. The pathological mechanisms of the disease are only partially understood. The hSOD1-G93A ALS rat model is characterized by an overexpression of human mutated SOD1, causing increased vulnerability by forming intracellular protein aggregates, inducing excitotoxicity, affecting oxidative balance and disturbing axonal transport. In this study we followed the bio-macromolecular organic composition and compartmentalization together with trace metal distribution in situ in single astrocytes from the ALS rat model and compared them to the control astrocytes from nontransgenic littermates by simultaneous use of two synchrotron radiation-based methods: Fourier transform infrared microspectroscopy (SR-FTIR) and hard Xray fluorescence microscopy (XRF). We show that ALS cells contained more Cu, which colocalized with total lipids, increased carbonyl groups and oxidized lipids, thus implying direct involvement of Cu in oxidative stress of lipidic components without direct connection to protein aggregation in situ.

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“…It has been shown that GAGs are involved in protein aggregation and prion diffusion ( [36][37][38][39][40][41][42][43][44] ). Lysosome activity changes were described in ALS caused by the C9orf72 gene repeat expansions ( [45][46][47][48][49] ), while synthesis of PA is linked to all types of phospholipids, including phosphatidylcholine and phosphatidylethanolamine that have been linked to ALS and prion disease pathogenesis ( 50,51 ).…”

Section: Functional Analysismentioning

confidence: 99%

Analysis of circulating protein aggregates reveals pathological hallmarks of amyotrophic lateral sclerosis

Adiutori

Puentes

Bremang

et al. 2020

Preprint

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Blood-based biomarkers can be informative of brain disorders where protein aggregation play a major role. The proteome of plasma and circulating protein aggregates (CPA) reflect the inflammatory and metabolic state of the organism and can be predictive of system-level and/or organ-specific pathologies. CPA are enriched with heavy chain neurofilaments (NfH), key axonal constituents involved in brain aggregates formation and biomarkers of the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Here we show that CPA and brain protein aggregates (BPA) from ALS differ in protein composition and appear as a combination of electron-dense large globular and small filamentous formations on transmission electron microscopy. CPA are highly enriched with proteins involved in the proteasome and energy metabolism. Compared to the human proteome, proteins within aggregates show distinct and tissue-dependent chemical features of aggregation propensity. The use of a TMTcalibrator™ proteomics workflow with ALS brain as calibrant reveals 4973 brain-derived low-abundance proteins in CPA, including the products of translation of 24 ALS risk genes. 285 of these (5.7%) are regulated in ALS CPA including FUS (p<0.05). CPA from both ALS and healthy controls affect cell viability when testing endothelial and PC12 neuronal cell lines, while CPA from ALS exert a more toxic effect at lower concentrations. The analysis of resistance to protease enzymes hydrolysis indicates an ALS-specific digestion pattern for NfH using enterokinase. This study reveals how peripheral protein aggregates are significantly enriched with brain proteins which are highly representative of ALS pathology and a potential alternative source of biomarkers and therapeutic targets for this incurable disorder.Significance StatementMolecular mechanism of neurodegeneration like protein aggregation are important brain-specific alterations which need to be addressed therapeutically. Recently described fluid biomarkers of neurodegenerative disorders provide means for stratification and monitoring of disease progression. Here we show that circulating protein aggregates are easily accessible in blood and reproduce important features of brain pathology for an incurable disorder like amyotrophic lateral sclerosis. They represent a source of biomarkers and of novel therapeutics for ALS.

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Lipidomics Reveals Cerebrospinal-Fluid Signatures of ALS

Cited by 120 publications

References 32 publications

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Lipids status and copper in a single astrocyte of the rat model for amyotrophic lateral sclerosis: Correlative synchrotron‐based X‐ray and infrared imaging

Analysis of circulating protein aggregates reveals pathological hallmarks of amyotrophic lateral sclerosis

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