The role of lipids in the central nervous system and their pathological implications in amyotrophic lateral sclerosis

Tracey, Timothy J.; Kirk, Siobhan; Steyn, Frederik J.; Ngo, Shyuan T.

doi:10.1016/j.semcdb.2020.08.012

Cited by 31 publications

(34 citation statements)

References 205 publications

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“…At the same time, we found halved amounts of two intermediates of glycerolipid metabolism (i.e., galactosyl-glycerol and phosphatidic acid). These results highlighted that alterations in lipid metabolism/signaling processes occur in ALS astrocytes, which are consistent with previously reported data [24,[82][83][84]. Interestingly, lipid handling from astrocytes to neurons plays an essential role not only as a source of energy, but also for mediating neural circuit formation and function [85].…”

Section: Discussionsupporting

confidence: 91%

Perturbations of the Proteome and of Secreted Metabolites in Primary Astrocytes from the hSOD1(G93A) ALS Mouse Model

Stella

Bonadio

Cagnin

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose pathophysiology is largely unknown. Despite the fact that motor neuron (MN) death is recognized as the key event in ALS, astrocytes dysfunctionalities and neuroinflammation were demonstrated to accompany and probably even drive MN loss. Nevertheless, the mechanisms priming astrocyte failure and hyperactivation are still obscure. In this work, altered pathways and molecules in ALS astrocytes were unveiled by investigating the proteomic profile and the secreted metabolome of primary spinal cord astrocytes derived from transgenic ALS mouse model overexpressing the human (h)SOD1(G93A) protein in comparison with the transgenic counterpart expressing hSOD1(WT) protein. Here we show that ALS primary astrocytes are depleted of proteins—and of secreted metabolites—involved in glutathione metabolism and signaling. The observed increased activation of Nf-kB, Ebf1, and Plag1 transcription factors may account for the augmented expression of proteins involved in the proteolytic routes mediated by proteasome or endosome–lysosome systems. Moreover, hSOD1(G93A) primary astrocytes also display altered lipid metabolism. Our results provide novel insights into the altered molecular pathways that may underlie astrocyte dysfunctionalities and altered astrocyte–MN crosstalk in ALS, representing potential therapeutic targets to abrogate or slow down MN demise in disease pathogenesis.

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Section: Discussionsupporting

confidence: 91%

Perturbations of the Proteome and of Secreted Metabolites in Primary Astrocytes from the hSOD1(G93A) ALS Mouse Model

Stella

Bonadio

Cagnin

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…By using a potent HDAC inhibitor, ACY-738, and by combining transcriptomic and lipidomic analysis, our data demonstrated a link between epigenetic modifications and lipid metabolism defects in the spinal cord of a FUS mouse model of ALS. While these two cellular processes appear to be commonly implicated in ALS pathology and actively participate in disease progression [ 11 , 25 ], our results highlight HDAC inhibition as a relevant potential therapeutic strategy to treat this devastating disease.…”

Section: Discussionmentioning

confidence: 90%

“…When studying lipids in ALS, deciphering the contribution of individual cell types to the pathological processes remains challenging [ 25 ]. Moreover, the observed phenotype could be directly related to neuron or glial cells biology/health or related to their changing proportions over disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies demonstrated the potential protective effect and benefit of lipids modifications in ALS [ 25 ]. The modulation of sphingolipids using different pharmacological agents has been shown to drive improvements in motor performances, protection of neuromuscular junctions, and prolong survival of SOD1 models [ 26 , 31 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…These results align with growing evidence demonstrating that lipid metabolism dysfunction is not just a consequence of disease progression but rather plays a causal role [ 22 , 23 , 24 ]. Dysfunctions of the lipid metabolism are observed in the central nervous system, blood, and muscles of ALS patients and different mouse models, often long before the appearance of motor symptoms [ 25 ]. Lipidomic analyses on these tissues showed alterations of numerous lipid classes such as sphingolipids, glycerophospholipids, cholesterols, and free fatty acids [ 26 , 27 , 28 , 29 , 30 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

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Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

Burg

Rossaert

Moisse

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disorder of the motor system. While the etiology is still incompletely understood, defects in metabolism act as a major contributor to the disease progression. Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been shown to restore metabolic alterations in the spinal cord of a FUS mouse model of ALS, which was accompanied by a beneficial effect on the motor phenotype and survival. In this study, we investigated the specific effects of HDAC inhibition on lipid metabolism using untargeted lipidomic analysis combined with transcriptomic analysis in the spinal cord of FUS mice. We discovered that symptomatic FUS mice recapitulate lipid alterations found in ALS patients and in the SOD1 mouse model. Glycerophospholipids, sphingolipids, and cholesterol esters were most affected. Strikingly, HDAC inhibition mitigated lipid homeostasis defects by selectively targeting glycerophospholipid metabolism and reducing cholesteryl esters accumulation. Therefore, our data suggest that HDAC inhibition is a potential new therapeutic strategy to modulate lipid metabolism defects in ALS and potentially other neurodegenerative diseases.

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Lipid Metabolism: Key Determinant in Neurodegenerative Diseases

Yadav,

Gupta,

Agrawal

2024

Altered Metabolism: A Major Contributor of Comorbidities in Neurodegenerative Diseases

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The role of lipids in the central nervous system and their pathological implications in amyotrophic lateral sclerosis

Cited by 31 publications

References 205 publications

Perturbations of the Proteome and of Secreted Metabolites in Primary Astrocytes from the hSOD1(G93A) ALS Mouse Model

Perturbations of the Proteome and of Secreted Metabolites in Primary Astrocytes from the hSOD1(G93A) ALS Mouse Model

Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

Lipid Metabolism: Key Determinant in Neurodegenerative Diseases

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