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Free Radic Biol Med. 2020 Feb 1. pii: S0891-5849(19)32464-5. doi: 10.1016/j.freeradbiomed.2020.01.177. [Epub ahead of print]

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

Author information

1
Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Spain.
2
Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Spain; CIBERER U759, Center for Biomedical Research on Rare Diseases, Spain.
3
Peroxisomal Diseases Laboratory, Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD, 21205, USA.
4
MRC Mitochondrial Biology Unit, Cambridge, UK.
5
Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193, Bellaterra (Barcelona), Spain.
6
Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío /CSIC/ Universidad de Sevilla, E-41013, Sevilla, Spain.
7
Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193, Bellaterra (Barcelona), Spain; Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), 08500, Vic, Spain. Electronic address: esther.dalfo@umedicina.cat.
8
Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Duran i Reynals, L'Hospitalet de Llobregat, Spain; CIBERER U759, Center for Biomedical Research on Rare Diseases, Spain; ICREA (Institució Catalana de Recerca i Estudis Avançats), Barcelona, Spain. Electronic address: apujol@idibell.cat.

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.

KEYWORDS:

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

Conflict of interest statement

Declaration of competing interest The authors declare no conflict of interest.

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