|Title||The peroxisomal fatty acid transporter ABCD1/PMP-4 is required in the C. elegans hypodermis for axonal maintenance: A worm model for adrenoleukodystrophy.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Coppa, A, Guha, S, Fourcade, S, Parameswaran, J, Ruiz, M, Moser, AB, Schlüter, A, Murphy, MP, Lizcano, JMiguel, Miranda-Vizuete, A, Dalfó, E, Pujol, A|
|Journal||Free Radic Biol Med|
|Date Published||2020 Feb 01|
Adrenoleukodystrophy is a neurometabolic disorder caused by a defective peroxisomal ABCD1 transporter of very long-chain fatty acids (VLCFAs). Its pathogenesis is incompletely understood. Here we characterize a nematode model of X-ALD with loss of the pmp-4 gene, the worm orthologue of ABCD1. These mutants recapitulate the hallmarks of X-ALD: i) VLCFAs accumulation and impaired mitochondrial redox homeostasis and ii) axonal damage coupled to locomotor dysfunction. Furthermore, we identify a novel role for PMP-4 in modulating lipid droplet dynamics. Importantly, we show that the mitochondria targeted antioxidant MitoQ normalizes lipid droplets size, and prevents axonal degeneration and locomotor disability, highlighting its therapeutic potential. Moreover, PMP-4 acting solely in the hypodermis rescues axonal and locomotion abnormalities, suggesting a myelin-like role for the hypodermis in providing essential peroxisomal functions for the nematode nervous system.
|Alternate Journal||Free Radic. Biol. Med.|