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Lipid alterations in human frontal cortex in ALS‐FTLD‐TDP43 proteinopathy spectrum are partly related to peroxisome impairment
Author(s) -
AndrésBenito Pol,
Gelpi Ellen,
Jové Mariona,
MotaMartorell Natalia,
Obis Èlia,
PorteroOtin Manuel,
Povedano Mònica,
Pujol Aurora,
Pamplona Reinald,
Ferrer Isidro
Publication year - 2021
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12681
Subject(s) - lipidome , lipid metabolism , biology , c9orf72 , peroxisome , amyotrophic lateral sclerosis , lipidomics , microbiology and biotechnology , neuroscience , biochemistry , gene , pathology , medicine , disease , trinucleotide repeat expansion , allele
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.