Abstract
X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disease caused by mutations in the ABCD1 gene, encoding a member of the peroxisomal ABC transporter family. The ABCD1 protein transports CoA-activated very long-chain fatty acids (VLCFAs) into peroxisomes for degradation via β-oxidation. In the severest form, X-ALD patients suffer from inflammatory demyelination of the brain. As the extent of the metabolic defect in the main immune cells is unknown, we explored their phenotypes concerning mRNA expression pattern of the three peroxisomal ABC transporters, VLCFA accumulation and peroxisomal β-oxidation. In controls, ABCD1 expression was high in monocytes, intermediate in B cells and low in T cells; ABCD2 expression was extremely low in monocytes, intermediate in B cells and highest in T cells; ABCD3 mRNA was equally distributed. In X-ALD patients, the expression patterns remained unaltered; accordingly, monocytes, which lack compensatory VLCFA transport by ABCD2, displayed the severest biochemical phenotype with a 6-fold accumulation of C26:0 and a striking 70% reduction in peroxisomal β-oxidation activity. In contrast, VLCFA metabolism was close to control values in B cells and T cells, supporting the hypothesis that sufficient ABCD2 is present to compensate for ABCD1 deficiency. Thus, the vulnerability of the main immune cell types is highly variable in X-ALD. Based on these results, we propose that in X-ALD the halt of inflammation after allogeneic hematopoietic stem cell transplantation relies particularly on the replacement of the monocyte lineage. Additionally, these findings support the concept that ABCD2 is a target for pharmacological induction as an alternative therapeutic strategy.
Highlights
X-linked adrenoleukodystrophy (X-ALD; Phenotype MIM number #300100), the most frequent monogenetically inherited peroxisomal disease, causes demyelinating and neurodegenerative processes in the nervous system (1 – 3)
In order to explore the biological relevance of ABCD1 in the major CD34+-derived immune cell types, we compared the basal ABCD1 mRNA levels with those of the other peroxisomal ATP-binding cassette (ABC) transporters, ABCD2 and ABCD3 in healthy male adults (25 – 48 years of age) by using quantitative reverse transcription-coupled PCR
ABCD1 mRNA levels were intermediate in B cells (CD19+) and lowest in natural killer (NK) cells (CD32/CD56+), NKT cells (CD3+/CD56+) and T cells (CD4+ and CD8+)
Summary
X-linked adrenoleukodystrophy (X-ALD; Phenotype MIM number #300100), the most frequent monogenetically inherited peroxisomal disease, causes demyelinating and neurodegenerative processes in the nervous system (1 – 3). AMN (mean age-of-onset 28 years) is thought to be the default manifestation of X-ALD, a slowly progressive non-inflammatory axonopathy involving the spinal cord and peripheral nerves. This results in a typical triad of spastic paraplegia, sensory involvement and bladder dysfunction [1]. In CALD, rapidly progressive, inflammatory cerebral demyelination occurs independently of AMN. CALD occurs during childhood before the onset of AMN (35 – 40%; mean age-of-onset 7 years) and less frequently (20%) in adolescent or adult AMN
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