IMMUNOLOCALIZATION OF A 43 KDA PEROXISOMAL MEMBRANE-PROTEIN IN THE LIVER OF PATIENTS WITH GENERALIZED PEROXISOMAL DISORDERS
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1995
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Abstract
The presence of peroxisomal membrane ghosts was examined in liver biopsies from eleven patients presenting the clinical and biochemical picture of a generalized peroxisomal disorder (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and variants of these syndromes). A polyclonal antibody raised against the membrane of human liver peroxisomes and recognizing a 43 kDa peroxisomal membrane protein (PMP) was used. In human control liver the antibodies react in a distinct and specific way with the peroxisomal membrane.
Two types of organelles with an immunoreactive membrane were identified in the liver parenchymal cells of the patients: organelles containing an electron-dense core and organelles with electron transparent contents. Both types may co-occur in the same patient; in two patients they were found in the same cell. The organelles are rare, and their number varies between patients. The first type possibly corresponds to the previous morphological description of aberrant peroxisomes in the liver of patients with Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease. The empty looking organelles have not been reported previously in the liver, some of the ''empty'' organelles seem to be enclosed by a double membrane.
Morphometrical analysis in three patients indicated that both types of organelles (corrected mean d-circle 0.271-0.306 mu m for the ''empty'' and the dense core organelles, respectively) are smaller than the peroxisomes in postnatal control liver and in fetal liver.
In one patient (infantile Refsum disease) immunoreactive organelles were not detected. The organelles with the electron-dense core were not found in two patients. In one of them, described clinically and biochemically as a mild Zellweger variant, very few cells showed numerous small organelles enclosing a morphologically normal matrix which contained at least the peroxisomal matrix proteins catalase, acyl-CoA oxidase, 3-ketoacyl-CoA thiolase, and alanine/glyoxylate aminotransferase; their membrane showed 43 kDa PMP immunoreactivity.
The dense core organelles and the empty-lookinig organelles were not found in human control livers, in which solely the membrane of normal peroxisomes was labeled. It is therefore suggested that both types of organelles, identified by their immunoreactivity for the 43 kDa PMP, represent aberrant peroxisomes. The finding of morphologically empty vesicles is in accordance with the concept that the defect in these disorders is at the level of the assembly of import competent peroxisomes. On the other hand, the findings also indicate that at least in one patient the defect is not present in all parenchymal cells: peroxisomes containing at least four matrix proteins mere present in a minority of the cells.
Two types of organelles with an immunoreactive membrane were identified in the liver parenchymal cells of the patients: organelles containing an electron-dense core and organelles with electron transparent contents. Both types may co-occur in the same patient; in two patients they were found in the same cell. The organelles are rare, and their number varies between patients. The first type possibly corresponds to the previous morphological description of aberrant peroxisomes in the liver of patients with Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease. The empty looking organelles have not been reported previously in the liver, some of the ''empty'' organelles seem to be enclosed by a double membrane.
Morphometrical analysis in three patients indicated that both types of organelles (corrected mean d-circle 0.271-0.306 mu m for the ''empty'' and the dense core organelles, respectively) are smaller than the peroxisomes in postnatal control liver and in fetal liver.
In one patient (infantile Refsum disease) immunoreactive organelles were not detected. The organelles with the electron-dense core were not found in two patients. In one of them, described clinically and biochemically as a mild Zellweger variant, very few cells showed numerous small organelles enclosing a morphologically normal matrix which contained at least the peroxisomal matrix proteins catalase, acyl-CoA oxidase, 3-ketoacyl-CoA thiolase, and alanine/glyoxylate aminotransferase; their membrane showed 43 kDa PMP immunoreactivity.
The dense core organelles and the empty-lookinig organelles were not found in human control livers, in which solely the membrane of normal peroxisomes was labeled. It is therefore suggested that both types of organelles, identified by their immunoreactivity for the 43 kDa PMP, represent aberrant peroxisomes. The finding of morphologically empty vesicles is in accordance with the concept that the defect in these disorders is at the level of the assembly of import competent peroxisomes. On the other hand, the findings also indicate that at least in one patient the defect is not present in all parenchymal cells: peroxisomes containing at least four matrix proteins mere present in a minority of the cells.
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Keywords
ZELLWEGER SYNDROME, LIVER, MEMBRANE PROTEIN, PEROXISOMES, PROTEIN IMPORT