TY - JOUR
T1 - The peroxisomal fatty acid transporter ABCD1/PMP-4 is required in the C. elegans hypodermis for axonal maintenance
T2 - A worm model for adrenoleukodystrophy
AU - Coppa, Andrea
AU - Guha, Sanjib
AU - Fourcade, Stéphane
AU - Parameswaran, Janani
AU - Ruiz, Montserrat
AU - Moser, Ann B.
AU - Schlüter, Agatha
AU - Murphy, Michael P.
AU - Lizcano, Jose Miguel
AU - Miranda-Vizuete, Antonio
AU - Dalfó, Esther
AU - Pujol, Aurora
N1 - Funding Information:
We thank CERCA Program/Generalitat de Catalunya for institutional support. Most of the strains were supplied by the Caenorhabditis Genetic Center (CGC). Plasmids HYM772 was kindly provided by Dr. Ho Yi Mak (Stowers Institute for Medical Research, Kansas City, MO, USA). We especially thank Dr. Marta Artal, Centro Andaluz de Biología del Desarrollo, Sevilla, Spain, for critical reading the manuscript. This work was supported by grants from the Autonomous Government of Catalonia [ 2017SGR1206 ] to A.P., The Spanish Ministry of Science and Competitivity grants ( PC0009/003 and PI1100968 to E. D). This study has been funded by Instituto de Salud Carlos III through the grants [Miguel Servet program CPII16/00016 ] to S.F. (Co-funded by European Social Fund . ESF investing in your future), and the Center for Biomedical Research on Rare Diseases (CIBERER) to A.P and M.R. S.G. was a fellow of the Autonomous Government of Catalonia [ 2014FI_B2 00028 ]. A.C. and J.P. were fellows of IDIBELL.
Funding Information:
We thank CERCA Program/Generalitat de Catalunya for institutional support. Most of the strains were supplied by the Caenorhabditis Genetic Center (CGC). Plasmids HYM772 was kindly provided by Dr. Ho Yi Mak (Stowers Institute for Medical Research, Kansas City, MO, USA). We especially thank Dr. Marta Artal, Centro Andaluz de Biolog?a del Desarrollo, Sevilla, Spain, for critical reading the manuscript. This work was supported by grants from the Autonomous Government of Catalonia [2017SGR1206] to A.P. The Spanish Ministry of Science and Competitivity grants (PC0009/003 and PI1100968 to E. D). This study has been funded by Instituto de Salud Carlos III through the grants [Miguel Servet program CPII16/00016] to S.F. (Co-funded by European Social Fund. ESF investing in your future), and the Center for Biomedical Research on Rare Diseases (CIBERER) to A.P and M.R. S.G. was a fellow of the Autonomous Government of Catalonia [2014FI_B2 00028]. A.C. and J.P. were fellows of IDIBELL.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/5/20
Y1 - 2020/5/20
N2 - 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.
AB - 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.
KW - Axonal degeneration
KW - Hypodermis
KW - Lipid droplets
KW - Mitochondria redox imbalance
KW - Peroxisomes
KW - X-linked adrenoleukodystrophy
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U2 - 10.1016/j.freeradbiomed.2020.01.177
DO - 10.1016/j.freeradbiomed.2020.01.177
M3 - Article
C2 - 32017990
AN - SCOPUS:85079056890
SN - 0891-5849
VL - 152
SP - 797
EP - 809
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -