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MMW Fortschritte Der Medizin Feb 2023
Topics: Humans; Adrenoleukodystrophy
PubMed: 36849777
DOI: 10.1007/s15006-023-2386-1 -
Journal of Inherited Metabolic Disease Jul 2015Peroxisomes and mitochondria are ubiquitous, highly dynamic organelles with an oxidative type of metabolism in eukaryotic cells. Over the years, substantial evidence has... (Review)
Review
Peroxisomes and mitochondria are ubiquitous, highly dynamic organelles with an oxidative type of metabolism in eukaryotic cells. Over the years, substantial evidence has been provided that peroxisomes and mitochondria exhibit a close functional interplay which impacts on human health and development. The so-called "peroxisome-mitochondria connection" includes metabolic cooperation in the degradation of fatty acids, a redox-sensitive relationship, an overlap in key components of the membrane fission machineries and cooperation in anti-viral signalling and defence. Furthermore, combined peroxisome-mitochondria disorders with defects in organelle division have been revealed. In this review, we present the latest progress in the emerging field of peroxisomal and mitochondrial interplay in mammals with a particular emphasis on cooperative fatty acid β-oxidation, redox interplay, organelle dynamics, cooperation in anti-viral signalling and the resulting implications for disease.
Topics: Animals; Fatty Acids; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Membranes; Oxidation-Reduction; Peroxisomal Disorders; Peroxisomes; Virus Diseases
PubMed: 25687155
DOI: 10.1007/s10545-015-9819-7 -
Advances in Experimental Medicine and... 2020Heimler syndrome is a rare syndrome associating sensorineural hearing loss with retinal dystrophy and amelogenesis imperfecta due to PEX1 or PEX6 biallelic pathogenic... (Review)
Review
Heimler syndrome is a rare syndrome associating sensorineural hearing loss with retinal dystrophy and amelogenesis imperfecta due to PEX1 or PEX6 biallelic pathogenic variations. This syndrome is one of the less severe forms of peroxisome biogenesis disorders. In this chapter, we will review clinical, biological, and genetic knowledges about the Heimler syndrome.
Topics: ATPases Associated with Diverse Cellular Activities; Amelogenesis Imperfecta; Hearing Loss, Sensorineural; Humans; Membrane Proteins; Nails, Malformed; Peroxisomal Disorders
PubMed: 33417209
DOI: 10.1007/978-3-030-60204-8_7 -
Journal of Inherited Metabolic Disease May 2021X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder affecting the adrenal glands, testes, spinal cord and brain. The disease is caused by mutations in the... (Review)
Review
X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder affecting the adrenal glands, testes, spinal cord and brain. The disease is caused by mutations in the ABCD1 gene resulting in a defect in peroxisomal degradation of very long-chain fatty acids and their accumulation in plasma and tissues. Males with ALD have a near 100% life-time risk to develop myelopathy. The life-time prevalence to develop progressive cerebral white matter lesions (known as cerebral ALD) is about 60%. Adrenal insufficiency occurs in about 80% of male patients. In adulthood, 80% of women with ALD also develop myelopathy, but adrenal insufficiency or cerebral ALD are very rare. The complex clinical presentation and the absence of a genotype-phenotype correlation are complicating our understanding of the disease. In an attempt to understand the pathophysiology of ALD various model systems have been developed. While these model systems share the basic genetics and biochemistry of ALD they fail to fully recapitulate the complex neurodegenerative etiology of ALD. Each model system recapitulates certain aspects of the disorder. This exposes the complexity of ALD and therefore the challenge to create a comprehensive model system to fully understand ALD. In this review, we provide an overview of the different ALD modeling strategies from single-celled to multicellular organisms and from in vitro to in vivo approaches, and introduce how emerging iPSC-derived technologies could improve the understanding of this highly complex disorder.
Topics: ATP Binding Cassette Transporter, Subfamily D, Member 1; Adrenoleukodystrophy; Adult; Animals; Biological Evolution; Fatty Acids; Female; Humans; Male; Models, Animal; Models, Biological; Mutation; Sex Factors; Spinal Cord Diseases
PubMed: 33373044
DOI: 10.1002/jimd.12357 -
Biochimica Et Biophysica Acta.... Feb 2020The type-2 peroxisomal targeting signal (PTS2) is one of two peptide motifs destining soluble proteins for peroxisomes. This signal acts as amphiphilic α-helix exposing... (Review)
Review
The type-2 peroxisomal targeting signal (PTS2) is one of two peptide motifs destining soluble proteins for peroxisomes. This signal acts as amphiphilic α-helix exposing the side chains of all conserved residues to the same side. PTS2 motifs are recognized by a bipartite protein complex consisting of the receptor PEX7 and a co-receptor. Cargo-loaded receptor complexes are translocated across the peroxisomal membrane by a transient pore and inside peroxisomes, cargo proteins are released and processed in many, but not all species. The components of the bipartite receptor are re-exported into the cytosol by a ubiquitin-mediated and ATP-driven export mechanism. Structurally, PTS2 motifs resemble other N-terminal targeting signals, whereas the functional relation to the second peroxisomal targeting signal (PTS1) is unclear. Although only a few PTS2-carrying proteins are known in humans, subjects lacking a functional import mechanism for these proteins suffer from the severe inherited disease rhizomelic chondrodysplasia punctata.
Topics: Amino Acid Motifs; Chondrodysplasia Punctata, Rhizomelic; Humans; Membrane Proteins; Peroxisomal Targeting Signal 2 Receptor; Peroxisomes; Protein Domains; Protein Structure, Quaternary; Protein Transport
PubMed: 31751594
DOI: 10.1016/j.bbamcr.2019.118609 -
Methods in Molecular Biology (Clifton,... 2017The peroxisomal disorders (PDs) are a heterogeneous group of genetic diseases in man caused by an impairment in peroxisome biogenesis or one of the metabolic functions... (Review)
Review
The peroxisomal disorders (PDs) are a heterogeneous group of genetic diseases in man caused by an impairment in peroxisome biogenesis or one of the metabolic functions of peroxisomes. Thanks to the revolutionary technical developments in gene sequencing methods and their increased use in patient diagnosis, the field of genetic diseases in general and peroxisomal disorders in particular has dramatically changed in the last few years. Indeed, several novel peroxisomal disorders have been identified recently and in addition it has been realized that the phenotypic spectrum of patients affected by a PD keeps widening, which makes clinical recognition of peroxisomal patients increasingly difficult. Here, we describe these new developments and provide guidelines for the clinical and laboratory diagnosis of peroxisomal patients.
Topics: Acyl-CoA Oxidase; Genetic Testing; Humans; Peroxisomal Disorders; Peroxisomal Multifunctional Protein-2; Peroxisomes; Phenotype
PubMed: 28409475
DOI: 10.1007/978-1-4939-6937-1_30 -
Development, Growth & Differentiation Jan 2024Inherited leukodystrophies are genetic disorders characterized by abnormal white matter in the central nervous system. Although individually rare, there are more than... (Review)
Review
Inherited leukodystrophies are genetic disorders characterized by abnormal white matter in the central nervous system. Although individually rare, there are more than 400 distinct types of leukodystrophies with a cumulative incidence of 1 in 4500 live births. The pathophysiology of most leukodystrophies is poorly understood, there are treatments for only a few, and there is significant morbidity and mortality, suggesting a critical need for improvements in this field. A variety of animal, cell, and induced pluripotent stem cell-derived models have been developed for leukodystrophies, but with significant limitations in all models. Many leukodystrophies lack animal models, and extant models often show no or mixed recapitulation of key phenotypes. Zebrafish (Danio rerio) have become increasingly used as disease models for studying leukodystrophies due to their early onset of disease phenotypes and conservation of molecular and neurobiological mechanisms. Here, we focus on reviewing new zebrafish disease models for leukodystrophy or models with recent progress. This includes discussion of leukodystrophy with vanishing white matter disease, X-linked adrenoleukodystrophy, Zellweger spectrum disorders and peroxisomal disorders, PSAP deficiency, metachromatic leukodystrophy, Krabbe disease, hypomyelinating leukodystrophy-8/4H leukodystrophy, Aicardi-Goutières syndrome, RNASET2-deficient cystic leukoencephalopathy, hereditary diffuse leukoencephalopathy with spheroids-1 (CSF1R-related leukoencephalopathy), and ultra-rare leukodystrophies. Zebrafish models offer important potentials for the leukodystrophy field, including testing of new variants in known genes; establishing causation of newly discovered genes; and early lead compound identification for therapies. There are also unrealized opportunities to use humanized zebrafish models which have been sparsely explored.
Topics: Animals; Zebrafish; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; Adrenoleukodystrophy; Leukoencephalopathies
PubMed: 38239149
DOI: 10.1111/dgd.12907 -
Topics in Magnetic Resonance Imaging :... Aug 2018Peroxisomes play vital roles in a broad spectrum of cellular metabolic pathways. Defects in genes encoding peroxisomal proteins can result in a wide array of disorders,... (Review)
Review
Peroxisomes play vital roles in a broad spectrum of cellular metabolic pathways. Defects in genes encoding peroxisomal proteins can result in a wide array of disorders, depending upon the metabolic pathways affected. These disorders can be broadly classified into 2 main groups; peroxisome biogenesis disorders (PBDs) and single peroxisomal enzyme deficiencies. Peroxisomal enzyme deficiencies are result of dysfunction of a specific metabolic pathway, while PBDs are due to generalized peroxisomal dysfunction. Mutations in PEX1 gene are the most common cause of PBDs, accounting for two-thirds of cases. Peroxisomal fission defects is a recently recognized entity, included under the subgroup of PBDs. The aim of this article is to provide a comprehensive review on the clinical and neuroimaging spectrum of peroxisomal disorders.
Topics: Brain; Humans; Magnetic Resonance Imaging; Neuroimaging; Peroxisomal Disorders
PubMed: 30086110
DOI: 10.1097/RMR.0000000000000172 -
Biochimica Et Biophysica Acta May 2016The peroxisomal compartment in hepatocytes hosts several essential metabolic conversions. These are defective in peroxisomal disorders that are either caused by failure... (Review)
Review
The peroxisomal compartment in hepatocytes hosts several essential metabolic conversions. These are defective in peroxisomal disorders that are either caused by failure to import the enzymes in the organelle or by mutations in the enzymes or in transporters needed to transfer the substrates across the peroxisomal membrane. Hepatic pathology is one of the cardinal features in disorders of peroxisome biogenesis and peroxisomal β-oxidation although it only rarely determines the clinical fate. In mouse models of these diseases liver pathologies also occur, although these are not always concordant with the human phenotype which might be due to differences in diet, expression of enzymes and backup mechanisms. Besides the morphological changes, we overview the impact of peroxisome malfunction on other cellular compartments including mitochondria and the ER. We further focus on the metabolic pathways that are affected such as bile acid formation, and dicarboxylic acid and branched chain fatty acid degradation. It appears that the association between deregulated metabolites and pathological events remains unclear.
Topics: Animals; Disease Models, Animal; Endoplasmic Reticulum; Gene Expression Regulation; Humans; Liver; Membrane Proteins; Metabolic Networks and Pathways; Mice; Mitochondria, Liver; Mutation; Peroxisomal Disorders; Peroxisomes; Protein Isoforms; Protein Transport; Signal Transduction
PubMed: 26453805
DOI: 10.1016/j.bbamcr.2015.09.035 -
Biomolecules Aug 2023X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the peroxisomal transporter ABCD1, resulting in the accumulation...
X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the peroxisomal transporter ABCD1, resulting in the accumulation of very long-chain fatty acids (VLCFA). Strongly affected cell types, such as oligodendrocytes, adrenocortical cells and macrophages, exhibit high cholesterol turnover. Here, we investigated how ABCD1 deficiency affects cholesterol metabolism in human X-ALD patient-derived fibroblasts and CNS tissues of Abcd1-deficient mice. Lipidome analyses revealed increased levels of cholesterol esters (CE), containing both saturated VLCFA and mono/polyunsaturated (V)LCFA. The elevated CE(26:0) and CE(26:1) levels remained unchanged in LXR agonist-treated Abcd1 KO mice despite reduced total C26:0. Under high-cholesterol loading, gene expression of SOAT1, converting cholesterol to CE and lipid droplet formation were increased in human X-ALD fibroblasts versus healthy control fibroblasts. However, the expression of NCEH1, catalysing CE hydrolysis and the cholesterol transporter ABCA1 and cholesterol efflux were also upregulated. Elevated Soat1 and Abca1 expression and lipid droplet content were confirmed in the spinal cord of X-ALD mice, where expression of the CNS cholesterol transporter Apoe was also elevated. The extent of peroxisome-lipid droplet co-localisation appeared low and was not impaired by ABCD1-deficiency in cholesterol-loaded primary fibroblasts. Finally, addressing steroidogenesis, progesterone-induced cortisol release was amplified in X-ALD fibroblasts. These results link VLCFA to cholesterol homeostasis and justify further consideration of therapeutic approaches towards reducing VLCFA and cholesterol levels in X-ALD.
Topics: Humans; Mice; Animals; Adrenoleukodystrophy; ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Fatty Acids; Homeostasis; Cholesterol
PubMed: 37759733
DOI: 10.3390/biom13091333