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Cerebellar pathology in aldr 2 / 2 mice at 20 months of age. ( B ) Loss of Purkinje cell somata evidenced by Nissl staining (arrowheads). ( D ) Focal loss of staining with anti-calbindin D28K in the aldr 2 / 2 mice. ( F ) Focal upregulations of GFAP expression in aldr 2 / 2 . ( H ) Strong reduction of non-phosphorylated neurofilaments in Purkinje cells was seen by staining with anti-SMI32. ( A , C , E and G ) Images from wild-type littermate controls. Scale bar: 50 m m.
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ATP-binding cassette (ABC) transporters facilitate unidirectional translocation of chemically diverse substances, ranging from peptides to lipids, across cell or organelle membranes. In peroxisomes, a subfamily of four ABC transporters (ABCD1 to ABCD4) has been related to fatty acid transport, because patients with mutations in ABCD1 (ALD gene) suf...
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... histological stainings (Nissl). At 12 months of age, the abcd22/2 cerebellum showed no major changes in appearance of the molecular, Purkinje cell and granule cell layers, as well as normal foliation and cytoarchi- tecture (data not shown). However, at 20 months of age, we detected gaps in the Purkinje cell monolayer in Nissl-stained sections ( Fig. 7A and B). Immunohistochemistry against cal- bindin (D28-K) confirmed atrophy or death of Purkinje cells (Fig. 7C and D). A clear reduction of non-phosphorylated neu- rofilaments in Purkinje cells (SMI 32 antibody) (23) indicated reduced dendritic arborization (Fig. 7E and F). Fibrillary acidic protein (GFAP)-staining revealed an increased fre- ...
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... of the molecular, Purkinje cell and granule cell layers, as well as normal foliation and cytoarchi- tecture (data not shown). However, at 20 months of age, we detected gaps in the Purkinje cell monolayer in Nissl-stained sections ( Fig. 7A and B). Immunohistochemistry against cal- bindin (D28-K) confirmed atrophy or death of Purkinje cells (Fig. 7C and D). A clear reduction of non-phosphorylated neu- rofilaments in Purkinje cells (SMI 32 antibody) (23) indicated reduced dendritic arborization (Fig. 7E and F). Fibrillary acidic protein (GFAP)-staining revealed an increased fre- quency of local spots of GFAP upregulation in the molecular layer of the cerebellum (Fig. 7E and F). These GFAP ...
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... age, we detected gaps in the Purkinje cell monolayer in Nissl-stained sections ( Fig. 7A and B). Immunohistochemistry against cal- bindin (D28-K) confirmed atrophy or death of Purkinje cells (Fig. 7C and D). A clear reduction of non-phosphorylated neu- rofilaments in Purkinje cells (SMI 32 antibody) (23) indicated reduced dendritic arborization (Fig. 7E and F). Fibrillary acidic protein (GFAP)-staining revealed an increased fre- quency of local spots of GFAP upregulation in the molecular layer of the cerebellum (Fig. 7E and F). These GFAP 'hot- spots' are likely to indicate a local degeneration of Purkinje cells with concomitant local reactive ...
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... of Purkinje cells (Fig. 7C and D). A clear reduction of non-phosphorylated neu- rofilaments in Purkinje cells (SMI 32 antibody) (23) indicated reduced dendritic arborization (Fig. 7E and F). Fibrillary acidic protein (GFAP)-staining revealed an increased fre- quency of local spots of GFAP upregulation in the molecular layer of the cerebellum (Fig. 7E and F). These GFAP 'hot- spots' are likely to indicate a local degeneration of Purkinje cells with concomitant local reactive ...
Citations
... Additionally, strong labeling for abcd2 was observed in the inner granular and Purkinje cell layers of the cerebellum. ABCD2 transcript RNA was found in the cerebral cortex, and this expression pattern of ABCD2 may be associated with glioblastomas [29]. However, our survival analysis of glioblastoma showed that patients with low expression had a higher survival rate, so we hypothesized that ABCD2 may be associated with tumors, but not affect and alter cancer progression through metabolism. ...
The proteins encoded by the ABCD2 gene are integral members of the ATP-binding cassette (ABC) transporter superfamily. Although ABCD2 plays a critical role in membrane trafficking, its function in cancer has not been reported so far. Therefore, we undertook a systematic investigation of the prognostic implications and potential immune functions of ABCD2 across distinct tumor types. Leveraging datasets from TCGA, UALCAN, cBioPortal, and cancerSEA, we conducted an extensive series of bioinformatics analyses to elucidate the prognostic relevance of ABCD2. Our findings revealed statistically significant differences in ABCD2 expression between most tumors and adjacent normal tissues. Furthermore, ABCD2 exhibited both positive and negative associations with the prognosis of various cancers.Intriguingly, GSEA enrichment analysis underscored a strong correlation between ABCD2 and immune-related functions. To validate this observation, we investigated the relationship between the transcription of ABCD2 and immune cells, and the results revealed a significant correlation between ABCD2 and various immune cells, such as B cells and natural killer cells.To elucidate the biological significance of ABCD2 in tumor development, we delved into single-cell sequencing data, gene mutations, and promoter methylation patterns. Lastly, our study identified two potential ABCD2-targeted drugs. Altogether, our findings position ABCD2 as a versatile prognostic marker across multiple malignancies and highlight its paramount importance in the realm of tumor immunotherapy.
... The transporter(s) that allow GSH/GSSG to go across the mammalian peroxisomal membrane remain(s) totally enigmatic. Despite the scarcity of transmembrane proteins in peroxisomes (reviewed in Ref. [69]), mice or mammalian cells lacking one of these proteins or possessing a severe mutation in the corresponding gene do not display signs of a general peroxisome deficiency [69,[78][79][80][81][82][83][84][85][86]. One possibility to explain these findings is that other peroxisomal antioxidant defenses (e.g., catalase) compensate the lack of glutathione in the organelle (see Ref. [36]). ...
Despite intensive research on peroxisome biochemistry, the role of glutathione in peroxisomal redox homeostasis has remained a matter of speculation for many years, and only recently has this issue started to be experimentally addressed. Here, we summarize and compare data from several organisms on the peroxisome-glutathione topic. It is clear from this comparison that the repertoire of glutathione-utilizing enzymes in peroxisomes of different organisms varies widely. In addition, the available data suggest that the kinetic connectivity between the cytosolic and peroxisomal pools of glutathione may also be different in different organisms, with some possessing a peroxisomal membrane that is promptly permeable to glutathione whereas in others this may not be the case. However, regardless of the differences, the picture that emerges from all these data is that glutathione is a crucial component of the antioxidative system that operates inside peroxisomes in all organisms.
... The metabolic function of the peroxisome relies on its interaction with various subcellular organelles, including mitochondria, which play a role in re-oxidizing the NADH produced during the peroxisomal beta-oxidation [108]. Morphological abnormalities of the mitochondria have been reported in ALD cell models, mice, and patients [109][110][111], highlighting the contribution of the mitochondria as an underlying pathological mechanism of peroxisomal disorders. The presence of an excess of VLCFA, mainly hexacosanoic acid (C26:0), a substrate of peroxisomal beta-oxidation, in ALD fibroblasts has been found to trigger oxidative stress and decrease the mitochondrial membrane potential [112]. ...
N-acetylcysteine (NAC), a precursor of cysteine and, thereby, glutathione (GSH), acts as an antioxidant through a variety of mechanisms, including oxidant scavenging, GSH replenishment, antioxidant signaling, etc. Owing to the variety of proposed targets, NAC has a long history of use as a prescription product and in wide-ranging applications that are off-label as an over-the-counter (OTC) product. Despite its discovery in the early 1960s and its development for various indications, systematic clinical pharmacology explorations of NAC pharmacokinetics (PK), pharmacodynamic targets, drug interactions, and dose-ranging are sorely limited. Although there are anecdotal instances of NAC benefits in a variety of diseases, a comprehensive review of the use of NAC in rare diseases does not exist. In this review, we attempt to summarize the existing literature focused on NAC explorations in rare diseases targeting mitochondrial dysfunction along with the history of NAC usage, approved indications, mechanisms of action, safety, and PK characterization. Further, we introduce the research currently underway on other structural derivatives of NAC and acknowledge the continuum of efforts through pre-clinical and clinical research to facilitate further therapeutic development of NAC or its derivatives for rare diseases.
... The second model was a double knockout of the Abcd1 and Abcd2 transporters (Abcd1 − /Abcd2 −/− or DKO). Compared with the Abcd1 − mice, DKO mice display greater VLCFA accumulation in the spinal cord [32,68], higher levels of oxidative damage to proteins [31], and a more severe AMNlike pathology with an earlier onset at 12 months of age [28,68], which makes this model better suited for preclinical therapeutic assays. We assessed the clinical signs of AMN in DKO mice. ...
Aberrant endocannabinoid signaling accompanies several neurodegenerative disorders, including multiple sclerosis. Here, we report altered endocannabinoid signaling in X-linked adrenoleukodystrophy (X-ALD), a rare neurometabolic demyelinating syndrome caused by malfunction of the peroxisomal ABCD1 transporter, resulting in the accumulation of very long-chain fatty acids (VLCFAs). We found abnormal levels of cannabinoid receptor 2 (CB2r) and related endocannabinoid enzymes in the brain and peripheral blood mononuclear cells (PBMCs) of X-ALD patients and in the spinal cord of a murine model of X-ALD. Preclinical treatment with a selective agonist of CB2r (JWH133) halted axonal degeneration and associated locomotor deficits, along with normalization of microgliosis. Moreover, the drug improved the main metabolic disturbances underlying this model, particularly in redox and lipid homeostatic pathways, including increased lipid droplets in motor neurons, through the modulation of the GSK-3β/NRF2 axis. JWH133 inhibited Reactive Oxygen Species elicited by excess VLCFAs in primary microglial cultures of Abcd1-null mice. Furthermore, we uncovered intertwined redox and CB2r signaling in the murine spinal cords and in patient PBMC samples obtained from a phase II clinical trial with antioxidants (NCT01495260). These findings highlight CB2r signaling as a potential therapeutic target for X-ALD and perhaps other neurodegenerative disorders that present with dysregulated redox and lipid homeostasis.
... ABCD1 mutations in humans cause the X-linked adrenoleukodystrophy; Abcd1 −/− mice display abnormal myelination, brain cell morphology, astrocytosis, axon degeneration, and impaired coordination. Interestingly, Abcd2 −/− mice manifest neuronal and axon degeneration, ataxia, hyperactivity, tremors, abnormal microglial cell morphology, posture, and coordination, suggesting that this protein also functions in the brain (Ferrer et al., 2005). A family with a bile acid synthesis defect and peroxisomal abnormalities displayed mutations in ABCD3(?). ...
The ATP‐binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra‐ and intra‐cellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport defects. To provide tools to study the function of human ABC transporters we compiled data from multiple genomics databases. We analyzed ABC gene conservation within human populations and across vertebrates surveyed phenotypes of ABC gene mutations in mice. Most mouse ABC gene disruption mutations have a phenotype that mimics human disease, indicating they are applicable models. Interestingly several ABCA family genes, whose human function is unknown, have cholesterol level phenotypes in the mouse. Genome‐wide association studies confirm and extend ABC traits and suggest several new functions to investigate. Whole exome sequencing of tumors from diverse cancer types demonstrates that mutations in ABC genes are not common in cancer, but specific genes are overexpressed in select tumor types. Finally, an analysis of the frequency of loss‐of‐function mutations demonstrates that many human ABC genes are essential with a low level of variants, while others have a higher level of genetic diversity. This article is protected by copyright. All rights reserved.
... ABCD1 mutations in humans cause the X-linked adrenoleukodystrophy; Abcd1 -/mice display abnormal myelination, brain cell morphology, astrocytosis, axon degeneration, and impaired coordination. Interestingly,Abcd2 -/mice manifest neuronal and axon degeneration, ataxia, hyperactivity, tremors, abnormal microglial cell morphology, posture, and coordination, suggesting that this protein also functions in the brain (Ferrer et al., 2005). A family with a bile acid synthesis defect and peroxisomal abnormalities displayed mutations in ABCD3(?). ...
The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra- and intra-cellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport defects. Common polymorphisms and rare variants in ABC genes are associated with several complex phenotypes such as gout, gallstones, and cholesterol levels. Overexpression or amplification of specific drug efflux genes contributes to chemotherapy multidrug resistance. Conservation of the ATP-binding domains of ABC transporters defines the superfamily members, and phylogenetic analysis groups the 48 human ABC transporters into seven distinct subfamilies. While the conservation of ABC genes across most vertebrate species is high, there is also considerable gene duplication, deletion, and evolutionary diversification.
... Peroxisomes execute essential cellular functions such as the breakdown (beta-oxidation) of fatty acids and the metabolism of reactive oxygen species (Castro et al., 2018). An interaction and cross talk between the Golgi and peroxisomes were previously suggested in both yeast and mammalian cells (Ferrer et al., 2005;Valm et al., 2017;Yofe et al., 2017). While PI4P at Golgi contacts serves as a biosensor for glucose levels and regulates the trafficking of nutrient transporters (Shin et al., 2020), peroxisome abundance was also shown to be regulated by the available carbon source (Yofe et al., 2017). ...
... The expression of ABCD2, a peroxisomal VLCFA transporter, is affected by cholesterol levels (Raas et al., 2019), in turn, regulated at Golgi contacts. Deletion of ABCD2 in mice caused accumulation of VLCFAs and disruption of the Golgi architecture which resulted in neurodegeneration (Ferrer et al., 2005). Moreover, ABCD2 is a homolog of ABCD1 (Ferrer et al., 2005), a peroxisome-LD contact protein (Chang et al., 2019), and although the two share partial functional redundancy, it seems that ABCD2 mediates another function that is yet to be discovered (Ferrer et al., 2005). ...
... Deletion of ABCD2 in mice caused accumulation of VLCFAs and disruption of the Golgi architecture which resulted in neurodegeneration (Ferrer et al., 2005). Moreover, ABCD2 is a homolog of ABCD1 (Ferrer et al., 2005), a peroxisome-LD contact protein (Chang et al., 2019), and although the two share partial functional redundancy, it seems that ABCD2 mediates another function that is yet to be discovered (Ferrer et al., 2005). Despite the lack of information that directly links the Golgi to peroxisomes, their involvement in similar metabolic pathways suggests such a contact would be beneficial. ...
Contact sites are areas of close apposition between two membranes that coordinate nonvesicular communication between organelles. Such interactions serve a wide range of cellular functions from regulating metabolic pathways to executing stress responses and coordinating organelle inheritance. The past decade has seen a dramatic increase in information on certain contact sites, mostly those involving the endoplasmic reticulum. However, despite its central role in the secretory pathway, the Golgi apparatus and its contact sites remain largely unexplored. In this review, we discuss the current knowledge of Golgi contact sites and share our thoughts as to why Golgi contact sites are understudied. We also highlight what exciting future directions may exist in this emerging field.
... In order to study the function of peroxisomal ABC transporters and the pathogenesis of X-ALD in integrated mammalian models, Abcd1-, Abcd2-, and Abcd3-deficient mouse models have been generated [33][34][35]40,67,126]. The Abcd1 knock-out mice show key biochemical features of X-ALD but develop a late onset progressive neurodegenerative phenotype involving the spinal cord and sciatic nerves without brain damage [127]. ...
ATP-binding cassette (ABC) transporters constitute one of the largest superfamilies of conserved proteins from bacteria to mammals. In humans, three members of this family are expressed in the peroxisomal membrane and belong to the subfamily D: ABCD1 (ALDP), ABCD2 (ALDRP), and ABCD3 (PMP70). These half-transporters must dimerize to form a functional transporter, but they are thought to exist primarily as tetramers. They possess overlapping but specific substrate specificity, allowing the transport of various lipids into the peroxisomal matrix. The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively. In addition to their role in peroxisome metabolism, it has recently been proposed that peroxisomal ABC transporters participate in cell signaling and cell control, particularly in cancer. This review presents an overview of the knowledge on the structure, function, and mechanisms involving these proteins and their link to pathologies. We summarize the different in vitro and in vivo models existing across the species to study peroxisomal ABC transporters and the consequences of their defects. Finally, an overview of the known and possible interactome involving these proteins, which reveal putative and unexpected new functions, is shown and discussed.
... Abcd1 KO mice reproduce the VLCFA accumulation characteristic of the human disease (40) and the failure in mitochondrial function in the spinal cord of AMN (51). The Abcd1/Abcd2 DKO additionally lack the ABCD2 transporter, the closest homolog that can partially compensate for the ABCD1 deficiency, and develop an earlier onset of motor impairment than the Abcd1 KO mice (at 14 versus 20 months) (52)(53)(54)(55). This model is more appropriate to study the effects of a drug in ameliorating motor dysfunction. ...
... Leriglitazone showed dose-dependent efficacy in correcting the motor dysfunction during the disease progression assessed by two different tests, the rotarod and the balance beam, in the Abcd1/Abcd2 DKO mice. These results provide support that However, although mouse lines with targeted KO of Abcd1 and Abcd1/Abcd2 have provided good models to investigate the pathogenesis of AMN, they do not develop the cerebral phenotype of X-ALD (41,(52)(53)(54)(55). The EAE model is widely used in MS research, and given the similarity of the neuroinflammation component of cALD and certain aspects of MS, it is proposed as a surrogate model for cALD. ...
X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive spinal cord axonopathy [adrenomyeloneuropathy (AMN)] to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. Leriglitazone is a recently developed brain penetrant full PPARγ agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased adenosine 5′-triphosphate concentration, and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long chain fatty acid–induced toxicity simulating X-ALD. In addition, leriglitazone improved motor function; restored markers of oxidative stress, mitochondrial function, and inflammation in spinal cord tissues from AMN mouse models; and decreased the neurological disability in the EAE neuroinflammatory mouse model. X-ALD monocyte–derived patient macrophages treated with leriglitazone were less skewed toward an inflammatory phenotype, and the adhesion of human X-ALD monocytes to brain endothelial cells decreased after treatment, suggesting the potential of leriglitazone to prevent the progression to pathologically disrupted blood-brain barrier. Leriglitazone increased myelin debris clearance in vitro and increased myelination and oligodendrocyte survival in demyelination-remyelination in vivo models, thus promoting remyelination. Last, leriglitazone was clinically tested in a phase 1 study showing central nervous system target engagement (adiponectin increase) and changes on inflammatory biomarkers in plasma and cerebrospinal fluid. The results of our study support the use of leriglitazone in X-ALD and, more generally, in other neuroinflammatory and neurodegenerative conditions.
... As ACBD5 might provide acyl-CoAs for peroxisomal ABCD transporters 11 , a comparison of ABCD-deficient and ACBD5-deficient mice could give further information on the pathology in ACBD5 deficiency. Abcd1 −/− and Abcd2 −/− mice develop a mild, late-onset cerebellar phenotype with partial loss in Purkinje cells and reactive gliosis at advanced ages of 20 and 12 months, respectively 45,46 . An Abcd1/Abcd2 double-knockout strain develops a more severe locomotor phenotype with changes in cerebellar morphology observed at 12 months 45 . ...
ACBD5 deficiency is a novel peroxisome disorder with a largely uncharacterized pathology. ACBD5 was recently identified in a tethering complex mediating membrane contacts between peroxisomes and the endoplasmic reticulum (ER). An ACBD5-deficient mouse was analyzed to correlate ACBD5 tethering functions with the disease phenotype. ACBD5-deficient mice exhibit elevated very long-chain fatty acid levels and a progressive cerebellar pathology. Liver did not exhibit pathologic changes but increased peroxisome abundance and drastically reduced peroxisome-ER contacts. Lipidomics of liver and cerebellum revealed tissue-specific alterations in distinct lipid classes and subspecies. In line with the neurological pathology, unusual ultra-long chain fatty acids (C > 32) were elevated in phosphocholines from cerebelli but not liver indicating an organ-specific imbalance in fatty acid degradation and elongation pathways. By contrast, ether lipid formation was perturbed in liver towards an accumulation of alkyldiacylglycerols. The alterations in several lipid classes suggest that ACBD5, in addition to its acyl-CoA binding function, might maintain peroxisome-ER contacts in order to contribute to the regulation of anabolic and catabolic cellular lipid pathways.
