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

Pol Andrés‐Benito,Natalia Mota‐Martorell,Èlia Obis,Isidro Ferrer,Ellen Gelpi,Mariona Jové,Manuel Portero‐Otin,Aurora Pujol,Reinald Pamplona,Mònica Povedano

doi:10.1111/nan.12681

Abstract

AimPeroxisomes 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.MethodsWe used transcriptomics and lipidomics methods to define the steady‐state levels of gene expression and lipid profiles.ResultsOur 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.ConclusionGlobally, 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.

Highlights

Peroxisomes are single membrane-bound cytoplasmic organelles in eukaryotic cells which harbour a variety of biochemical reactions and metabolic pathways involved in oxidative stress homeostasis, and carbohydrate, amino acid and lipid metabolism
The biogenesis of peroxisomes requires a group of proteins named peroxins, encoded by PEX genes, which participate in the formation of peroxisomal membranes incorporating peroxisomal membrane proteins, peroxisome proliferator-activated receptors that modulate peroxisomal biogenesis and regulate lipid metabolism, and dynamin-related proteins [6, 7, 18,19,20,21]
ACAA1 gene expression was decreased in sporadic Amyotrophic lateral sclerosis (ALS) (sALS) and sFTLD-TDP when compared with controls (p < 0.001 and p < 0.001 respectively), but it was increased in c9FTLD, when compared with controls (p < 0.001), and with respect to sALS (p < 0.001) and sFTLD-TDP cases (p < 0.001)

Summary

Introduction

Peroxisomes are single membrane-bound cytoplasmic organelles in eukaryotic cells which harbour a variety of biochemical reactions and metabolic pathways involved in oxidative stress homeostasis, and carbohydrate, amino acid and lipid metabolism. Primary peroxisomal defects of lipid metabolism are genetically determined disorders linked to mutations of specific peroxisomal genes that lead to distinct diseases with neurologic and systemic manifestations and invariably poor outcomes These may affect fatty acid β-oxidation, ether lipid biosynthesis and fatty acid α-oxidation [11, 22,23,24,25,26,27,28,29,30,31]. Accumulation of C22:0 and very long-chain fatty acids, and decreased levels of plasmalogens, together with increased volume density and loss of peroxisomes in neurons with neurofibrillary tangles, are all observed with AD progression [39] These alterations have prompted the study of several specific therapeutic tools directed to curbing altered peroxisomal function in AD [40,41,42,43,44,45]

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