Lipid Metabolic Alterations in the ALS-FTD Spectrum of Disorders

Abstract

There is an increasing interest in the study of the relation between alterations in systemic lipid metabolism and neurodegenerative disorders, in particular in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). In ALS these alterations are well described and evident not only with the progression of the disease but also years before diagnosis. Still, there are some discrepancies in findings relating to the causal nature of lipid metabolic alterations, partly due to the great clinical heterogeneity in ALS. ALS presentation is within a disorder spectrum with Frontotemporal Dementia (FTD), and many patients present mixed forms of ALS and FTD, thus increasing the variability. Lipid metabolic and other systemic metabolic alterations have not been well studied in FTD, or in ALS-FTD mixed forms, as has been in pure ALS. With the recent development in lipidomics and the integration with other -omics platforms, there is now emerging data that not only facilitates the identification of biomarkers but also enables understanding of the underlying pathological mechanisms. Here, we reviewed the recent literature to compile lipid metabolic alterations in ALS, FTD, and intermediate mixed forms, with a view to appraising key commonalities or differences within the spectrum.

Keywords: ALS; FTD; cholesterol; lipid metabolism; lipidomics.

Figure 1

Schematic representation of the major lipid classes and their relations. The relationships between the main categories of mammalian lipids, starting with the 2-carbon precursor acetyl CoA, which is the basis for fatty acid biosynthesis, have been observed. Fatty acyls, in turn, through various modifications, give rise to complex lipids, such as sphingolipids, glycerolipids, glycerophospholipids, and sterols. Another route to generate other classes of lipids from acetyl-CoA is through isopentenyl pyrophosphate, which provides the building blocks for prenols and sterol lipids. Finally, the biosynthesis from acetyl-CoA, via conversion to malonyl-CoA, gives rise to polyketides. Saccharolipids are an unrelated group of lipids that are found in bacteria. The arrows denote multi-step transformations between the main lipid categories from acetyl CoA, isopentenyl pyrophosphate, and malonyl-CoA. The values in the green ovals represent the number of lipid structures curated within each lipid category. Below each lipid class are examples of the most representative molecules of the group (Adapted from Quehenberger et al. JLR 2010 [2]).

Figure 2

Lipid metabolic clinical features in the ALS–FTD spectrum of disorders. Schematic representation of the main clinical features analysed in ALS and FTD patients in relation to lipid metabolism and the techniques used for those analysis (created with Biorender).

Figure 3

Schematic representation of the main body weight and adiposity features in the patients of the ALS–FTD spectrum of disorders (created with Biorender).