Cerebral Iron Accumulation Is Not a Major Feature of FA2H/SPG35.
Ontology highlight
ABSTRACT:
SUBMITTER: Marelli C
PROVIDER: S-EPMC6353525 | biostudies-literature | 2015 Mar
REPOSITORIES: biostudies-literature
Publications
Cerebral Iron Accumulation Is Not a Major Feature of <i>FA2H</i>/SPG35.
Marelli Cecilia C Salih Mustafa A MA Nguyen Karine K Mallaret Martial M Leboucq Nicolas N Hassan Hamdy H HH Drouot Nathalie N Labauge Pierre P Koenig Michel M
Movement disorders clinical practice 20150218 1
Mutations in the fatty-acid 2-hydroxylase (<i>FA2H</i>) gene cause an autosomal recessive spastic paraplegia (SPG35), often associating with cerebellar ataxia; cerebral MRI may show iron accumulation in the basal ganglia, leading to the inclusion of SPG35 among the causes of neurodegeneration with brain iron accumulation. This finding was initially considered strongly relevant for diagnosis, although its frequency is not yet established. We found 5 novel patients (from two families) with mutatio ...[more]
Similar Datasets
Project description:Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult-onset parkinsonism-dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA.Using autozygosity mapping and candidate gene sequencing, we identified mutations in the fatty acid hydroxylase gene FA2H, newly implicating abnormalities of ceramide metabolism in the pathogenesis of NBIA.Neuroimaging demonstrated T2 hypointensity in the globus pallidus, confluent T2 white matter hyperintensities, and profound pontocerebellar atrophy in affected members of two families. Phenotypically, affected family members exhibited spastic quadriparesis, ataxia, and dystonia with onset in childhood and episodic neurological decline. Analogous to what has been reported previously for PLA2G6, the phenotypic spectrum of FA2H mutations is diverse based on our findings and those of prior investigators, because FA2H mutations have been identified in both a form of hereditary spastic paraplegia (SPG35) and a progressive familial leukodystrophy.These findings link white matter degeneration and NBIA for the first time and implicate new signaling pathways in the genesis of NBIA.
| S-EPMC6059612 | biostudies-literature
Project description:Lung cancer causes more deaths than any other cancer. Sphingolipids encompass metabolically interconnected species whose balance has pivotal effects on proliferation, migration, and apoptosis. In this study, we paralleled quantification of sphingolipid species with quantitative (q)PCR analyses of metabolic enzymes in order to identify dysregulated routes of sphingolipid metabolism in different subtypes of lung cancers. Lung samples were submitted to histopathological reexamination in order to confirm cancer type/subtype, which included adenocarcinoma histological subtypes and squamous cell and neuroendocrine carcinomas. Compared with benign lesions and tumor-free parenchyma, all cancers featured decreased sphingosine-1-phosphate and SMs. qPCR analyses evidenced differential mechanisms leading to these alterations between cancer types, with neuroendocrine carcinomas upregulating SGPL1, but CERT1 being downregulated in adenocarcinomas and squamous cell carcinomas. 2-Hydroxyhexosylceramides (2-hydroxyHexCers) were specifically increased in adenocarcinomas. While UDP-glycosyltransferase 8 (UGT8) transcript levels were increased in all cancer subtypes, fatty acid 2-hydroxylase (FA2H) levels were higher in adenocarcinomas than in squamous and neuroendocrine carcinomas. As a whole, we report differing mechanisms through which all forms of lung cancer achieve low SM and lysosphingolipids. Our results also demonstrate that FA2H upregulation is required for the accumulation of 2-hydroxyHexCers in lung cancers featuring high levels of UGT8.
| S-EPMC6795083 | biostudies-literature
Project description:BackgroundIn Alzheimer's disease (AD), cerebral iron accumulation colocalizes with the pathological proteins amyloid-β (Aβ) and tau. Furthermore, tau-induced cortical thinning is associated with cognitive decline. In this study, quantitative susceptibility mapping (QSM) was used to investigate the whole-brain distribution pattern of cortical iron deposition and its relationships with cognition and cortical thickness in AD.MethodsThis cross-sectional study prospectively recruited 30 participants with AD and 26 age- and sex-matched healthy controls (HCs). All participants underwent QSM and T1-weighted examinations on a 3.0T MRI scanner. Global cognition was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Whole-brain cross-sectional QSM analysis and whole-brain QSM regression analyses against the MMSE and MoCA scores were performed. Surface-based morphometry analysis was also performed. Subsequently, in regions with significant atrophy, magnetic susceptibility was compared between the AD and HC groups, and the association between magnetic susceptibility and cortical thickness was assessed.ResultsWhole-brain QSM cross-sectional analysis in the AD group demonstrated widespread increased susceptibility across the cortical ribbon, asymmetrically covering the left hemisphere cerebral cortex, caudate nucleus, putamen, and partial cerebellar cortex. Whole-brain QSM regression analyses in the AD group showed that increased susceptibility covaried with lower MMSE and MoCA scores, and was predominantly located in the right parietal cortex and lateral occipital cortex. In the AD group, cortical thickness was reduced in the left superior temporal gyrus, right frontal pole, fusiform gyus, and pars opercularis, and there were increases in susceptibility in the right frontal pole (AD: mean ± SD 0.034±0.007 ppm, 95% CI: 0.032-0.037 ppm; HC: 0.030±0.005 ppm, 95% CI: 0.028-0.032 ppm; P=0.016) and pars opercularis (AD: 0.020±0.003 ppm, 95% CI: 0.018-0.021 ppm; HC: 0.017±0.002 ppm, 95% CI: 0.017-0.018 ppm; P=0.002). Susceptibility was negatively correlated with cortical thickness in the right pars opercularis in the entire cohort (r=-0.521, P<0.001) and AD group (r=-0.510, P=0.005).ConclusionsWidespread cortical iron, as measured by QSM, accumulated in AD and iron deposition was associated with poor cognitive performance. Increased iron content was also associated with brain atrophy. Our study suggests QSM may be a useful imaging biomarker for monitoring the neurodegenerative progression of AD.
| S-EPMC9403583 | biostudies-literature
Project description:Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson's disease, Friedreich's disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood-brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.
| S-EPMC9138489 | biostudies-literature
Project description:BackgroundWidespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD.MethodsWe searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells.ResultsOne heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells.ConclusionsWhile our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.
| S-EPMC4219428 | biostudies-literature
Project description:Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately 0.3-0.5% of the population and is characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Cerebral cavernous malformation is a genetic disease that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Causative loss-of-function mutations have been identified in three genes, KRIT1 (CCM1), CCM2 (MGC4607), and PDCD10 (CCM3), which occur in both sporadic and familial forms. Autophagy is a bulk degradation process that maintains intracellular homeostasis and that plays essential quality control functions within the cell. Indeed, several studies have identified the association between dysregulated autophagy and different human diseases. Here, we show that the ablation of the KRIT1 gene strongly suppresses autophagy, leading to the aberrant accumulation of the autophagy adaptor p62/SQSTM1, defective quality control systems, and increased intracellular stress. KRIT1 loss-of-function activates the mTOR-ULK1 pathway, which is a master regulator of autophagy, and treatment with mTOR inhibitors rescues some of the mole-cular and cellular phenotypes associated with CCM. Insufficient autophagy is also evident in CCM2-silenced human endothelial cells and in both cells and tissues from an endothelial-specific CCM3-knockout mouse model, as well as in human CCM lesions. Furthermore, defective autophagy is highly correlated to endothelial-to-mesenchymal transition, a crucial event that contributes to CCM progression. Taken together, our data point to a key role for defective autophagy in CCM disease pathogenesis, thus providing a novel framework for the development of new pharmacological strategies to prevent or reverse adverse clinical outcomes of CCM lesions.
| S-EPMC4644374 | biostudies-literature
Project description:Iron is essential for most living organisms. Plants transcriptionally induce genes involved in iron acquisition under conditions of low iron availability, but the nature of the deficiency signal and its sensors are unknown. Here we report the identification of new iron regulators in rice, designated Oryza sativa Haemerythrin motif-containing Really Interesting New Gene (RING)- and Zinc-finger protein 1 (OsHRZ1) and OsHRZ2. OsHRZ1, OsHRZ2 and their Arabidopsis homologue BRUTUS bind iron and zinc, and possess ubiquitination activity. OsHRZ1 and OsHRZ2 are susceptible to degradation in roots irrespective of iron conditions. OsHRZ-knockdown plants exhibit substantial tolerance to iron deficiency, and accumulate more iron in their shoots and grains irrespective of soil iron conditions. The expression of iron deficiency-inducible genes involved in iron utilization is enhanced in OsHRZ-knockdown plants, mostly under iron-sufficient conditions. These results suggest that OsHRZ1 and OsHRZ2 are iron-binding sensors that negatively regulate iron acquisition under conditions of iron sufficiency.
| S-EPMC3905729 | biostudies-literature
Project description:Several distinct congenital disorders can lead to tissue-iron overload with anemia. Repeated blood transfusions are one of the major causes of iron overload in several of these disorders, including ?-thalassemia major, which is characterized by a defective ?-globin gene. In this state, hyperabsorption of iron is also observed and can significantly contribute to iron overload. In ?-thalassemia intermedia, which does not require blood transfusion for survival, hyperabsorption of iron is the leading cause of iron overload. The mechanism of increased iron absorption in ?-thalassemia is unclear. We definitively demonstrate, using genetic mouse models, that intestinal hypoxia-inducible factor-2? (HIF2?) and divalent metal transporter-1 (DMT1) are activated early in the pathogenesis of ?-thalassemia and are essential for excess iron accumulation in mouse models of ?-thalassemia. Moreover, thalassemic mice with established iron overload had significant improvement in tissue-iron levels and anemia following disruption of intestinal HIF2?. In addition to repeated blood transfusions and increased iron absorption, chronic hemolysis is the major cause of tissue-iron accumulation in anemic iron-overload disorders caused by hemolytic anemia. Mechanistic studies in a hemolytic anemia mouse model demonstrated that loss of intestinal HIF2?/DMT1 signaling led to decreased tissue-iron accumulation in the liver without worsening the anemia. These data demonstrate that dysregulation of intestinal hypoxia and HIF2? signaling is critical for progressive iron overload in ?-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders.
| S-EPMC3864280 | biostudies-literature
Project description:Neuropathology plays a key role in characterizing the pathogenesis of neurodegenerative diseases including forms of neurodegeneration with brain iron accumulation (NBIA). Despite important differences, several genetically diverse forms of NBIA nevertheless share common features in addition to iron deposition, such as the presence of neuroaxonal spheroids. Multiple forms of NBIA also demonstrate tau or synuclein pathology, suggesting parallels with both Alzheimer and Parkinson diseases. This chapter summarizes what has been learned from the study of human patient tissues. Gross and microscopic findings are delineated, and similarities and differences between forms of NBIA are presented. Neuropathologic findings often help characterize fundamental features of disease and provide a springboard for more focused hypothesis-driven studies. Lessons learned from neuropathology thus contribute much to the characterization of the molecular mechanisms of disease.
| S-EPMC4429307 | biostudies-literature
Project description:Neurodegeneration with brain iron accumulation (NBIA) encompasses a group of inherited disorders that share the clinical features of an extrapyramidal movement disorder accompanied by varying degrees of intellectual disability and abnormal iron deposition in the basal ganglia. The genetic basis of ten forms of NBIA is now known. The clinical features of NBIA range from rapid global neurodevelopmental regression in infancy to mild parkinsonism with minimal cognitive impairment in adulthood, with wide variation seen between and within the specific NBIA sub-type. This review describes the clinical presentations, imaging findings, pathologic features, and treatment considerations for this heterogeneous group of disorders.
| S-EPMC4298713 | biostudies-literature