Lipid-induced endoplasmic reticulum stress in X-linked adrenoleukodystrophy

Abstract

X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease that is caused by mutations in the ABCD1 gene and characterized by elevated levels of very long-chain fatty acids (VLCFA) in plasma and tissues, with the most pronounced increase in the central nervous system. Virtually all male patients develop adrenal insufficiency and myelopathy (adrenomyeloneuropathy), but a subset develops a fatal cerebral demyelinating disease (known as cerebral ALD). Female patients may also develop myelopathy, but adrenal insufficiency or leukodystrophy are very rare. ALD has been associated with mitochondrial dysfunction, oxidative stress and bioenergetic failure, but the mechanism by which VLCFA accumulation triggers these effects has not been resolved thus far. In this study, we used primary human fibroblasts from normal subjects and ALD patients to investigate whether VLCFA can induce endoplasmic reticulum stress. We show that saturated VLCFA (C26:0) induce endoplasmic reticulum stress in fibroblasts from ALD patients, but not in controls. Furthermore, there is a clear correlation between the chain-length of the fatty acid and the induction of endoplasmic reticulum stress. Exposure of ALD fibroblasts to C26:0, resulted in increased expression of additional endoplasmic reticulum stress markers (EDEM1, GADD34 and CHOP) and in lipoapoptosis. This new insight into the underlying mechanism of VLCFA-induced toxicity is of great importance for the development of a disease modifying treatment for ALD aimed at the normalization of VLCFA levels in tissues.

Functional Peroxisomes Are Essential for Efficient Cholesterol Sensing and Synthesis

“…Another explanation for why no ER stress and UPR activation was observed in peroxisome-deficient CHO cells, in contrast to, e.g., postnatal Pex2 –/– mouse tissues or biopsies obtained from patients with peroxisomal disorders ( Kovacs et al, 2009 , 2012 ; Launay et al, 2017 ), might be the lack of accumulation of ER stress-inducing metabolites. Indeed, it has been shown that ER stress and UPR are induced in human primary skin fibroblast cell lines from X-linked adrenoleukodystrophy patients with ABCD1 mutations and impaired peroxisomal β-oxidation only after incubation with very long-chain fatty acids ( van de Beek et al, 2017 ). All three parallel branches of the UPR− governed by the ER-stress sensors IRE1, PERK, and ATF6, respectively, are activated upon pharmacologically induced ER stress ( Lin et al, 2007 ; Zhang et al, 2015 ).…”

Modeling and rescue of defective blood–brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients

“…Increased insulin-like growth factor receptor signaling in the ccALD-iBMECs indicated by our transcriptome analysis further hints at metabolic dysfunction as a factor contributing to the ccALD phenotype. Another study by van de Beek et al [ 96 ] showed that exposure of X-ALD fibroblasts to VLCFAs resulted in endoplasmic reticulum stress correlated with an increase in lipid droplet deposition. Both studies suggest that VLCFA accumulation would precede lipid droplet accumulation.…”

Aberrant regulation of the GSK ‐3β/ NRF 2 axis unveils a novel therapy for adrenoleukodystrophy

“…Primary fibroblasts from X-ALD patients provide a good surrogate cell model to dissect disease mechanisms, as they recapitulate the main disease hallmarks: accumulation of VLCFA (Moser et al, 1980), higher production of free radicals of mitochondrial origin (Lopez-Erauskin et al, 2013), loss of energetic homeostasis , altered proteostasis (Launay et al, 2013(Launay et al, , 2015, and endoplasmic reticulum (ER) stress (van de Beek et al, 2017;Launay et al, 2017). Using this cell system, we determined whether patients' fibroblasts exhibited an altered AKT/GSK-3b/NRF2 pathway.…”