Peroxisomal disorders in neurology

Abstract

SUMMARYAlthough peroxisomes were initially believed to play only a minor role in mammalian metabolism, it is now clear that they catalyse essential reactions in a number of different metabolic pathways and thus play an indispensable role in intermediary metabolism. The metabolic pathways in which peroxisomes are involved include the biosynthesis of ether phospholipids and bile acids, the oxidation of very long chain fatty acids, prostaglandins and unsaturated long chain fatty acids and the catabolism of phytanate and (in man) pipecolate and glyoxylate.The importance of peroxisomes in cellular metabolism is stressed by the existence of a group of inherited diseases, the peroxisomal disorders, caused by an impairment in one or more peroxisomal functions. In the last decade our knowledge about peroxisomes and peroxisomal disorders has progressed enormously and has been the subject of several reviews. New developments include the identification of several additional peroxisomal disorders, the discovery of the primary defect in several of these peroxisomal disorders, the recognition of novel peroxisomal functions and the application of complementation analysis to obtain information on the genetic relationship between the different peroxisomal disorders.The peroxisomal disorders recognized at present comprise 12 different diseases, with neurological involvement in 10 of them. These diseases include: (1) those in which peroxisomes are virtually absent leading to a generalized impairment of peroxisomal functions (the cerebro-hepato-renal syndrome of Zellweger, neonatal adrenoleukodystrophy, infantile Refsum disease and hyperpipecolic acidaemia); (2) those in which peroxisomes are present and several peroxisomal functions are impaired (the rhizomelic form of chondrodysplasia punctata, combined peroxisomal fl-oxidation enzyme protein deficiency); and (3)those in which peroxisomes are present and only a single peroxisomal function is impaired (X-linked adrenoleukodystrophy, peroxisomal thiolase deficiency (pseudo-Zellweger syndrome), acyl-CoA oxidase deficiency (pseudoneonatal adrenoleukodystrophy) and probably, the classic form of Refsum disease.

Isolation of peroxisome assembly mutants from Saccharomyces cerevisiae with different morphologies using a novel positive selection procedure.

“…The phenotypes of yeast cells showing a total absence of peroxisomes or the presence of peroxisomes at quite reduced levels resemble the phenotypes of cells isolated from patients suffering from the Zellweger syndrome. The phenotype of pas 7, which contains peroxisomes that contain at least catalase but not 3-ketoacylCoA thiolase, resembles another human peroxisome disorder, the Rhizomelic form of Chondrodysplasia punctata (Wanders et al, 1988). These yeast mutants may therefore prove useful as model systems for the study of human peroxisome disorders and will undoubtedly add to our present knowledge of the different aspects of peroxisome biogenesis.…”

“…This is due to a still rudimentary knowledge of peroxisomal protein routing compared to other cellular compartments and to the existence of human genetic disorders, collectively known as the cerebro-hepato-renal or Zellweger syndrome, in which the biogenesis of peroxisomes appears to be disturbed. Patients with this syndrome have severe clinical symptoms and may die within the first year after birth (for a review see Wanders, 1988). The disease is characterized at the cellular level by a diminished number or virtual absence of morphologically distinguishable peroxisomes.…”

PAS10 is a tetratricopeptide-repeat protein that is essential for the import of most matrix proteins into peroxisomes of Saccharomyces cerevisiae.

“…An understanding of these peroxisomal diseases at the molecular level is hampered by lack of knowledge about the maintenance and formation of the organelles and the still incomplete inventory oftheir enzymatic content (reviewed in refs. [1][2][3].…”

Hansenula polymorpha: An attractive model organism for molecular studies of peroxisome biogenesis and function

“…This multi-functionality of microbodies is unique among subcellular organelles in eukaryotes. Their importance in cellular metabolism may be stressed by the fact that peroxisomal dysfunction often leads to metabolic abnormalities and may be lethal, particularly in man (Zellweger syndrome; [5]). …”