Deciphering Lipid Dysregulation in ALS: from Mechanisms to Translational Medicine

Overview

Journal Transl Neurodegener

Publisher Biomed Central

Date 2022 Nov 8

PMID 36345044

Authors

Ira Agrawal

Yong Shan Lim

Shi-Yan Ng

Shuo-Chien Ling

Affiliations

Soon will be listed here.

Abstract

Lipids, defined by low solubility in water and high solubility in nonpolar solvents, can be classified into fatty acids, glycerolipids, glycerophospholipids, sphingolipids, and sterols. Lipids not only regulate integrity and fluidity of biological membranes, but also serve as energy storage and bioactive molecules for signaling. Causal mutations in SPTLC1 (serine palmitoyltransferase long chain subunit 1) gene within the lipogenic pathway have been identified in amyotrophic lateral sclerosis (ALS), a paralytic and fatal motor neuron disease. Furthermore, lipid dysmetabolism within the central nervous system and circulation is associated with ALS. Here, we aim to delineate the diverse roles of different lipid classes and understand how lipid dysmetabolism may contribute to ALS pathogenesis. Among the different lipids, accumulation of ceramides, arachidonic acid, and lysophosphatidylcholine is commonly emerging as detrimental to motor neurons. We end with exploring the potential ALS therapeutics by reducing these toxic lipids.

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References

Brodovitch A, Boucraut J, Delmont E, Parlanti A, Grapperon A, Attarian S . Combination of serum and CSF neurofilament-light and neuroinflammatory biomarkers to evaluate ALS. Sci Rep. 2021; 11(1):703. PMC: 7803734. DOI: 10.1038/s41598-020-80370-6. View

Chang M, Kwak S, Park J, Park D . Relationship between statins and the risk of amyotrophic lateral sclerosis: A PRISMA-compliant meta-analysis. Medicine (Baltimore). 2021; 100(30):e26751. PMC: 8322535. DOI: 10.1097/MD.0000000000026751. View

Aureli M, Mauri L, Ciampa M, Prinetti A, Toffano G, Secchieri C . GM1 Ganglioside: Past Studies and Future Potential. Mol Neurobiol. 2015; 53(3):1824-1842. DOI: 10.1007/s12035-015-9136-z. View

Feldman E, Goutman S, Petri S, Mazzini L, Savelieff M, Shaw P . Amyotrophic lateral sclerosis. Lancet. 2022; 400(10360):1363-1380. PMC: 10089700. DOI: 10.1016/S0140-6736(22)01272-7. View

Pandey M, Jabre N, Xu Y, Zhang W, Setchell K, Grabowski G . Gaucher disease: chemotactic factors and immunological cell invasion in a mouse model. Mol Genet Metab. 2013; 111(2):163-71. DOI: 10.1016/j.ymgme.2013.09.002. View

Funfschilling U, Jockusch W, Sivakumar N, Mobius W, Corthals K, Li S . Critical time window of neuronal cholesterol synthesis during neurite outgrowth. J Neurosci. 2012; 32(22):7632-45. PMC: 6703588. DOI: 10.1523/JNEUROSCI.1352-11.2012. View

Pelled D, Raveh T, Riebeling C, Fridkin M, Berissi H, Futerman A . Death-associated protein (DAP) kinase plays a central role in ceramide-induced apoptosis in cultured hippocampal neurons. J Biol Chem. 2001; 277(3):1957-61. DOI: 10.1074/jbc.M104677200. View

Goutman S, Boss J, Guo K, Alakwaa F, Patterson A, Kim S . Untargeted metabolomics yields insight into ALS disease mechanisms. J Neurol Neurosurg Psychiatry. 2020; 91(12):1329-1338. PMC: 7677469. DOI: 10.1136/jnnp-2020-323611. View

Pryce G, Baker D . Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Handb Exp Pharmacol. 2015; 231:213-31. DOI: 10.1007/978-3-319-20825-1_7. View

10.

Dyall S . Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA. Front Aging Neurosci. 2015; 7:52. PMC: 4404917. DOI: 10.3389/fnagi.2015.00052. View

11.

Suzuki S, Yamatoya H, Sakai M, Kataoka A, Furushiro M, Kudo S . Oral administration of soybean lecithin transphosphatidylated phosphatidylserine improves memory impairment in aged rats. J Nutr. 2001; 131(11):2951-6. DOI: 10.1093/jn/131.11.2951. View

12.

Renton A, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs J . A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011; 72(2):257-68. PMC: 3200438. DOI: 10.1016/j.neuron.2011.09.010. View

13.

Drachman D, Frank K, Dykes-Hoberg M, Teismann P, Almer G, Przedborski S . Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann Neurol. 2002; 52(6):771-8. DOI: 10.1002/ana.10374. View

14.

Dawson G, Stefansson K . Gangliosides of human spinal cord: aberrant composition of cords from patients with amyotrophic lateral sclerosis. J Neurosci Res. 1984; 12(2-3):213-20. DOI: 10.1002/jnr.490120209. View

15.

Vane J, Bakhle Y, Botting R . Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol. 1998; 38:97-120. DOI: 10.1146/annurev.pharmtox.38.1.97. View

16.

Bazinet R, Laye S . Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci. 2014; 15(12):771-85. DOI: 10.1038/nrn3820. View

17.

Sarbu M, Ica R, Zamfir A . Gangliosides as Biomarkers of Human Brain Diseases: Trends in Discovery and Characterization by High-Performance Mass Spectrometry. Int J Mol Sci. 2022; 23(2). PMC: 8775466. DOI: 10.3390/ijms23020693. View

18.

Martin E, Schule R, Smets K, Rastetter A, Boukhris A, Loureiro J . Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet. 2013; 92(2):238-44. PMC: 3567271. DOI: 10.1016/j.ajhg.2012.11.021. View

19.

Ziff O, Clarke B, Taha D, Crerar H, Luscombe N, Patani R . Meta-analysis of human and mouse ALS astrocytes reveals multi-omic signatures of inflammatory reactive states. Genome Res. 2021; 32(1):71-84. PMC: 8744676. DOI: 10.1101/gr.275939.121. View

20.

Moreno-Martet M, Espejo-Porras F, Fernandez-Ruiz J, de Lago E . Changes in endocannabinoid receptors and enzymes in the spinal cord of SOD1(G93A) transgenic mice and evaluation of a Sativex(®) -like combination of phytocannabinoids: interest for future therapies in amyotrophic lateral sclerosis. CNS Neurosci Ther. 2014; 20(9):809-15. PMC: 6493201. DOI: 10.1111/cns.12262. View