PUBLICATION
A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement for abcd1 in oligodendrocyte patterning and myelination
- Authors
- Strachan, L.R., Stevenson, T.J., Freshner, B., Keefe, M.D., Miranda Bowles, D., Bonkowsky, J.L.
- ID
- ZDB-PUB-170916-8
- Date
- 2017
- Source
- Human molecular genetics 26: 3600-3614 (Journal)
- Registered Authors
- Bonkowsky, Joshua, Keefe, Matthew
- Keywords
- none
- MeSH Terms
-
- ATP Binding Cassette Transporter, Subfamily D, Member 1/genetics
- ATP Binding Cassette Transporter, Subfamily D, Member 1/metabolism*
- ATP-Binding Cassette Transporters/genetics
- Adrenoleukodystrophy/genetics*
- Adrenoleukodystrophy/metabolism
- Alleles
- Animals
- Cells, Cultured
- Disease Models, Animal
- Exons
- Fatty Acids/genetics
- Fatty Acids/metabolism
- Genetic Diseases, X-Linked/genetics
- Genetic Diseases, X-Linked/metabolism
- Humans
- Mutation
- Myelin Sheath/genetics
- Myelin Sheath/metabolism
- Oligodendroglia/metabolism
- Zebrafish
- PubMed
- 28911205 Full text @ Hum. Mol. Genet.
Citation
Strachan, L.R., Stevenson, T.J., Freshner, B., Keefe, M.D., Miranda Bowles, D., Bonkowsky, J.L. (2017) A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement for abcd1 in oligodendrocyte patterning and myelination. Human molecular genetics. 26:3600-3614.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping