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

Andrea Coppa, Sanjib Guha, Stéphane Fourcade, Janani Parameswaran, Montserrat Ruiz, Ann B. Moser, Agatha Schlüter, Michael P. Murphy, Jose Miguel Lizcano, Antonio Miranda-Vizuete, Esther Dalfó, Aurora Pujol*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

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.

Original languageAmerican English
Pages (from-to)797-809
Number of pages13
JournalFree Radical Biology and Medicine
Volume152
DOIs
Publication statusPublished - 20 May 2020

Keywords

  • Axonal degeneration
  • Hypodermis
  • Lipid droplets
  • Mitochondria redox imbalance
  • Peroxisomes
  • X-linked adrenoleukodystrophy

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