A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement for abcd1 in oligodendrocyte patterning and myelination

Abstract

X-linked adrenoleukodystrophy (ALD) is a devastating inherited neurodegenerative disease caused by defects in the ABCD1 gene and affecting peripheral and central nervous system myelin. ABCD1 encodes a peroxisomal transmembrane protein required for very long chain fatty acid (VLCFA) metabolism. We show that zebrafish (Danio rerio) Abcd1 is highly conserved at the amino acid level with human ABCD1, and during development is expressed in homologous regions including the central nervous system and adrenal glands. We used TALENs to generate five zebrafish abcd1 mutant allele lines introducing premature stop codons in exon 1, as well as obtained an abcd1 allele from the Zebrafish Mutation Project carrying a point mutation in a splice donor site. Similar to patients with ALD, zebrafish abcd1 mutants have elevated VLCFA levels. Interestingly, we found that CNS development of the abcd1 mutants is disrupted, with hypomyelination in the spinal cord, abnormal patterning and decreased numbers of oligodendrocytes, and increased cell death. By day of life five abcd1 mutants demonstrate impaired motor function, and overall survival to adulthood of heterozygous and homozygous mutants is decreased. Expression of human ABCD1 in oligodendrocytes rescued apoptosis in the abcd1 mutant. In summary, we have established a zebrafish model of ALD that recapitulates key features of human disease pathology and which reveals novel features of underlying disease pathogenesis.

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

“…Functionally, the fish demonstrate impaired motor function and a decrease in overall survival. Induction of human ABCD1 expression in oligodendrocytes reduced embryonic apoptosis of these cells and improved motor function (Strachan et al, ).…”

“…species such as the drosophilae, mouse and zebra fish, the equivalent ABCD1 gene has been successfully targeted to generate knock-out models, each providing a unique strength and limitation (Forss-Petter et al, 1997;Gordon, Valdez, & Letsou, 2018;Kobayashi, Shinnoh, Kondo, & Yamada, 1997;Lu et al, 1997;Strachan et al, 2017).…”

Translational Metabolism: A multidisciplinary approach towards precision diagnosis of inborn errors of metabolism in the omics era

“…Especially for IEMs displaying neurological features, zebrafish has turned out to be a powerful model organism because zebrafish have a blood‐brain barrier and white matter. Strachan et al have recently described a zebrafish model for XALD, which, better than the previously reported mouse models, recapitulates key features of XALD including disrupted CNS development, hypomyelination of the spinal cord, abnormal patterning and decreased numbers of oligodendrocytes, and increased cell death . Another example of the power of zebrafish is work done by Pena et al who described a zebrafish model for pyridoxine‐dependent epilepsy (PDE) due to mutations in the gene ALDH7A1 which codes for an enzyme in the lysine degradation route .…”

Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

“…Adrenoleukodystrophy (ADL) is another X-linked neurodegenerative disease. Caused by mutations in the ABCD1 gene (Strachan et al, 2017), it affects the myelin of central and peripheral nervous systems. Mutations in ABCD1 cause a spectrum of phenotypes ranging from cerebral forms of infantile adrenoleukodystrophy to adenomyeloneuropathy mimicking HSP.…”

“…Mutations in ABCD1 cause a spectrum of phenotypes ranging from cerebral forms of infantile adrenoleukodystrophy to adenomyeloneuropathy mimicking HSP. Zebrafish models of ADL were created by Strachan et al (2017) through transcription activator-like effector nucleases in exon 1 of abcd1 (abcd1 zc90 ) and these authors also characterized a mutant model from the Zebrafish Mutation Project with a point mutation in abcd1 exon 9 (abcd1 sa509 ) (Strachan et al, 2017). The abcd1 sa509 mutant showed increased levels of very long chain fatty acids in 7-8 dpf larvae, reduced myelinization of axons in 5 dpf larvae, and increased apoptosis in the brain at 72 hpf, not observed in abcd1 zc90 mutants (Strachan et al, 2017).…”