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Pharmacological induction of peroxisomes in peroxisome biogenesis disorders
Author(s) -
Wei Heming,
Kemp Stephan,
McGuinness Martina C.,
Moser Ann B.,
Smith Kirby D.
Publication year - 2000
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/1531-8249(200003)47:3<286::aid-ana3>3.0.co;2-b
Subject(s) - peroxisome , peroxisomal disorder , biogenesis , zellweger syndrome , peroxisome proliferator , peroxisome proliferator activated receptor gamma , chemistry , microbiology and biotechnology , biology , biochemistry , receptor , gene
Inherited aberrant peroxisome assembly results in a group of neurological diseases termed peroxisome biogenesis disorders (PBDs). PBDs include three major clinical phenotypes that represent a continuum of clinical features from the most severe form, Zellweger syndrome (ZS), through neonatal adrenoleukodystrophy (NALD) to the least severe form, infantile Refsum's disease (IRD). Somatic cell complementation studies have identified 13 PBD complementation groups, each representing a defect in a peroxisomal protein (peroxin) involved in peroxisome biogenesis. Most complementation groups include a range of clinical phenotypes. In this study, peroxisome numbers were determined in fibroblasts from 29 PBD (ZS, NALD, and IRD) patients, with various phenotypes from nine complementation groups, using antibodies against either a peroxisomal membrane protein (anti‐Pex14p) or peroxisomal matrix proteins (anti‐SKL). A correlation between the number of peroxisomes, determined with either antibody, and PBD phenotype was found, suggesting that induction of peroxisome number might have a favorable effect on PBD. After treatment of PBD fibroblasts with sodium 4‐phenylbutyrate, a human peroxisome proliferator, there was an approximate twofold increase in peroxisome number. After 4‐phenylbutyrate treatment, an increase in transcription of the adrenoleukodystrophy‐related gene and the peroxin gene, PEX11α, was found in PBD fibroblasts. In NALD and IRD, but not ZS, fibroblasts there was an increase in very‐long‐chain fatty acid β‐oxidation and plasmalogen concentrations, and a decrease in very‐long‐chain fatty acid concentrations. These data suggest that pharmacological agents that induce peroxisome proliferation, such as 4‐phenylbutyrate, may have therapeutic potential in the treatment of PBD patients with milder phenotypes (NALD and IRD). Ann Neurol 2000;47:286–296