The peroxisomal fatty acid transporter ABCD1/PMP-4 is required in the C. elegans hypodermis for axonal maintenance: A worm model for adrenoleukodystrophy.

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Coppa, Andrea 
Guha, Sanjib 
Fourcade, Stéphane 
Parameswaran, Janani 
Ruiz, Montserrat 

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.

Axonal degeneration, Hypodermis, Lipid droplets, Mitochondria redox imbalance, Peroxisomes, X-linked adrenoleukodystrophy, ATP Binding Cassette Transporter, Subfamily D, Member 1, ATP-Binding Cassette Transporters, Adrenoleukodystrophy, Animals, Caenorhabditis elegans, Fatty Acids, Mice, Mice, Knockout, Subcutaneous Tissue
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Free Radic Biol Med
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Elsevier BV
Medical Research Council (MC_UU_00015/3)
Wellcome Trust (110159/Z/15/Z)