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.