Lipid alterations in human frontal cortex in ALS-FTLD-TDP43 proteinopathy spectrum are partly related to peroxisome impairment

Abstract

Aim: Peroxisomes play a key role in lipid metabolism, and peroxisome defects have been associated with neurodegenerative diseases such as X-adrenoleukodystrophy and Alzheimer's disease. This study aims to elucidate the contribution of peroxisomes in lipid alterations of area 8 of the frontal cortex in the spectrum of TDP43-proteinopathies. Cases of frontotemporal lobar degeneration-TDP43 (FTLD-TDP), manifested as sporadic (sFTLD-TDP) or linked to mutations in various genes including expansions of the non-coding region of C9ORF72 (c9FTLD), and of sporadic amyotrophic lateral sclerosis (sALS) as the most common TDP43 proteinopathies, were analysed.

Methods: We used transcriptomics and lipidomics methods to define the steady-state levels of gene expression and lipid profiles.

Results: Our results show alterations in gene expression of some components of peroxisomes and related lipid pathways in frontal cortex area 8 in sALS, sFTLD-TDP and c9FTLD. Additionally, we identify a lipidomic pattern associated with the ALS-FTLD-TDP43 proteinopathy spectrum, notably characterised by down-regulation of ether lipids and acylcarnitine among other lipid species, as well as alterations in the lipidome of each phenotype of TDP43 proteinopathy, which reveals commonalities and disease-dependent differences in lipid composition.

Conclusion: Globally, lipid alterations in the human frontal cortex of the ALS-FTLD-TDP43 proteinopathy spectrum, which involve cell membrane composition and signalling, vulnerability against cellular stress and possible glucose metabolism, are partly related to peroxisome impairment.

Keywords: fatty acid profiling; human frontal cortex; lipidomics; peroxisomes; plasmalogens; transcriptomics.

FIGURE 1

mRNA expression levels of peroxisome‐related genes in frontal cortex area 8 in controls, sALS, sFTLD‐TDP and c9FTLD cases assessed with TaqMan RT‐qPCR assays. (A) Genes implicated in peroxisome biogenesis. (B) Genes coding for redox mechanisms. (C) Genes involved in peroxisomal primary bile acid biosynthesis. (D) Genes related with peroxisome substrate transport. (E) Genes involved in peroxisomal β‐oxidation. Genes linked to plasmalogens biosynthesis (F) and acylcarnitine biosynthesis (G). Data are expressed as the mean values±SEM. The significance level was set at *p < 0.05, **p < 0.01 and ***p < 0.001 versus control group; ^# p < 0.05, ^## p < 0.01 and ^### p < 0.001 versus sALS; and ^$ p < 0.05, ^$$ p < 0.01 and ^$$$ p < 0.001 versus sFTLD‐TDP

FIGURE 2

mRNA expression levels of genes linked to fatty acid metabolism in frontal cortex area 8 in controls, sALS, sFTLD‐TDP and c9FTLD cases assessed with TaqMan RT‐qPCR assays. Data are expressed as the mean values±SEM. The significance level was set at *p < 0.05, **p < 0.01 and ***p < 0.001 versus control group; ^# p < 0.05, ^## p < 0.01 and ^### p < 0.001 versus sALS; and ^$ p < 0.05, ^$$ p < 0.01 and ^$$$ p < 0.001 versus sFTLD‐TDP

FIGURE 3

Multivariate statistics and learning methods reveal a specific lipidome shared by TDP‐43 proteinopathies. (A) Principal component analysis (PCA) 2D plot of samples lipidome. (B–C) Heatmap representation of hierarchical clustering of individual samples according to the top 25 statistically significantly different lipid species between (B) neurological disorders versus controls and (C) among groups of TDP‐43 proteinopathies. (D–E) Heatmap representation of hierarchical clustering of groups according to the identified significantly different lipid species (D) among groups of TDP‐43 proteinopathies and (E) between neurological disorders and controls