Multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis

Katherine Phan; Ying He; Surabhi Bhatia; Russell Pickford; Gordon McDonald; Srestha Mazumder; Hannah C Timmins; John R Hodges; Olivier Piguet; Nicolas Dzamko; Glenda M Halliday; Matthew C Kiernan; Woojin Scott Kim

doi:10.1093/braincomms/fcac340

Multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis

Brain Commun. 2022 Dec 26;5(1):fcac340. doi: 10.1093/braincomms/fcac340. eCollection 2023.

Authors

Katherine Phan^{1

2}, Ying He^{1

2}, Surabhi Bhatia^{1

2}, Russell Pickford³, Gordon McDonald⁴, Srestha Mazumder¹, Hannah C Timmins¹, John R Hodges¹, Olivier Piguet^{1

5}, Nicolas Dzamko^{1

2}, Glenda M Halliday^{1

2}, Matthew C Kiernan^{1

6}, Woojin Scott Kim^{1

2}

Affiliations

¹ The University of Sydney, Brain and Mind Centre, Sydney, NSW, Australia.
² The University of Sydney, School of Medical Sciences, Sydney, NSW, Australia.
³ Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW, Australia.
⁴ The University of Sydney, Sydney Informatics Hub, Sydney, NSW, Australia.
⁵ The University of Sydney, School of Psychology, Sydney, NSW, Australia.
⁶ Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Abstract

Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and loss of various muscular functions. Dyslipidaemia is prevalent in amyotrophic lateral sclerosis with aberrant changes mainly in cholesterol ester and triglyceride. Despite this, little is known about global lipid changes in amyotrophic lateral sclerosis or in relation to disease progression. The present study incorporated a longitudinal lipidomic analysis of amyotrophic lateral sclerosis serum with a comparison with healthy controls using advanced liquid chromatography-mass spectrometry. The results established that diglyceride, the precursor of triglyceride, was enriched the most, while ceramide was depleted the most in amyotrophic lateral sclerosis compared with controls, with the diglyceride species (18:1/18:1) correlating significantly to neurofilament light levels. The prenol lipid CoQ₈ was also decreased in amyotrophic lateral sclerosis and correlated to neurofilament light levels. Most interestingly, the phospholipid phosphatidylethanolamine and its three derivatives decreased with disease progression, in contrast to changes with normal ageing. Unsaturated lipids that are prone to lipid peroxidation were elevated with disease progression with increases in the formation of toxic lipid products. Furthermore, in vitro studies revealed that phosphatidylethanolamine synthesis modulated TARDBP expression in SH-SY5Y neuronal cells. Finally, diglyceride, cholesterol ester and ceramide were identified as potential lipid biomarkers for amyotrophic lateral sclerosis diagnosis and monitoring disease progression. In summary, this study represents a longitudinal lipidomics analysis of amyotrophic lateral sclerosis serum and has provided new insights into multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.

Keywords: amyotrophic lateral sclerosis; biomarkers; lipidomics.