RESUMO
FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). METHODS: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. RESULTS: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. CONCLUSION: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders.
Assuntos
Proteínas F-Box/genética , Distúrbios do Metabolismo do Ferro , Distrofias Neuroaxonais , Transtornos Parkinsonianos , Complexo de Endopeptidases do Proteassoma/metabolismo , Adulto , Consanguinidade , Epilepsia/enzimologia , Epilepsia/genética , Epilepsia/patologia , Epilepsia/fisiopatologia , Feminino , Humanos , Distúrbios do Metabolismo do Ferro/enzimologia , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/patologia , Distúrbios do Metabolismo do Ferro/fisiopatologia , Distrofias Neuroaxonais/enzimologia , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/patologia , Distrofias Neuroaxonais/fisiopatologia , Paraplegia/enzimologia , Paraplegia/genética , Paraplegia/patologia , Paraplegia/fisiopatologia , Transtornos Parkinsonianos/enzimologia , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Degenerações Espinocerebelares/enzimologia , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/patologia , Degenerações Espinocerebelares/fisiopatologia , Síndrome , Adulto JovemRESUMO
Ceruloplasmin, a multi-copper oxidase with four active copper atoms, oxidizes Fe2+ to Fe3+ and concomittantly fully reduces oxygen to water. The oxygenation of iron is a requisite for transferrin transport of iron and keeping noxious Fe2+ low. In the central nervous system (CNS) Cp is mostly localized in end feet of astrocytes surrounding capillaries and attached by a glycosylphosphatidylinositol-anchor. In aceruloplasminaemia, a rare recessive hereditary disease, complete loss of Cp is accompanied by disorders of iron metabolism and lesions in CNS and outside. In PD Cp concentration and oxidative activity in serum are significantly lowered with iron deposits and lesions in substantia nigra and basal ganglia. Changes in Cp-genes might be causative in these disorders. By inducing neuromelanin synthesis Cp may protect neurons in substantia nigra. In AD Cp activity in serum, but not concentration, is significantly lowered. Changes in Cp-genes have not been verified in AD. Total amounts of iron are not increased in AD brains although iron deposits and cortical lesions are numerous. Total copper is significantly lowered in AD brains. This may result in defective synthesis of Cp and other copper enzymes. - In conclusion, the defective Cp activity, associated with iron disorders, is seemingly of importance in PD and also in AD with other copper enzyme defects possibly involved.
Assuntos
Doença de Alzheimer/enzimologia , Encéfalo/enzimologia , Ceruloplasmina/metabolismo , Ferro/metabolismo , Doença de Parkinson/enzimologia , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Encéfalo/patologia , Ceruloplasmina/deficiência , Ceruloplasmina/genética , Humanos , Ferro/sangue , Distúrbios do Metabolismo do Ferro/enzimologia , Distúrbios do Metabolismo do Ferro/genética , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/genética , Oxirredução , Doença de Parkinson/sangue , Doença de Parkinson/patologiaRESUMO
Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic inclusions (Lewy bodies). Iron, which is elevated in the substantia nigra (SN) of PD patients, seems to be of pivotal importance, because of its capacity to enhance the amplification of reactive-oxygen species. Therefore, it is tempting that the iron-releasing key enzyme in heme catabolism, heme oxygenase-1 (HO-1), may represent a candidate for a genetic susceptibility to PD. In the current study, we examined a (GT)n fragment length polymorphism in the promoter region, as well as three coding SNPs in the HO-1 gene in order to assess if certain genotypes are associated with PD. Furthermore, peripheral blood expression levels of HO-1 in PD patients and healthy probands were compared. However, our analyses did not reveal a significant association of these genetic markers in the HO-1 gene with an increased susceptibility to PD.
Assuntos
Predisposição Genética para Doença/genética , Heme Oxigenase-1/genética , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética , Substância Negra/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Análise Mutacional de DNA , Éxons/genética , Feminino , Frequência do Gene , Marcadores Genéticos/fisiologia , Testes Genéticos , Genótipo , Heme Oxigenase-1/sangue , Humanos , Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/complicações , Distúrbios do Metabolismo do Ferro/enzimologia , Distúrbios do Metabolismo do Ferro/genética , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Regiões Promotoras Genéticas/genética , Substância Negra/fisiopatologiaRESUMO
To identify novel genes associated with iron metabolism, we performed gene chip studies in two models of iron deficiency: iron-deprived rats and rats deficient in the principal intestinal iron transporter, divalent metal transporter 1 (i.e., Belgrade rats). Affymetrix rat genome gene chips were utilized (RAE230) with cRNA samples derived from duodenum and jejunum of experimental and control animals. Computational analysis and statistical data reduction identified 29 candidate genes, which were induced in both models of iron deficiency. Gene ontology analysis showed enrichment for genes related to lipid homeostasis, and one gene related to this physiological process, a leukocyte type, arachidonate 12-lipoxygenase (Alox15), was selected for further examination. TaqMan real-time PCR studies demonstrated strong induction of Alox15 throughout the small and large intestine, and in the liver of iron-deficient rats. Polyclonal antibodies were developed and utilized to demonstrate that proteins levels are significantly increased in the intestinal epithelium of iron-deprived rats. HPLC analysis revealed altered intestinal lipid metabolism indicative of Alox15 activity, which resulted in the production of biologically active lipid molecules (12-HETE, 13-HODE, and 13-HOTE). The overall effect is a perturbation of intestinal lipid homeostasis, which results in the production of lipids essentially absent in the intestine of control rats. We have thus provided mechanistic insight into the alteration in lipid metabolism that occurs during iron deficiency, in that induction of Alox15 mRNA expression may be the primary event. The resulting lipid mediators may be related to documented alterations in villus structure and cell proliferation rates in iron deficiency, or to structural alterations in membrane lipid composition.
Assuntos
Araquidonato 12-Lipoxigenase/biossíntese , Araquidonato 15-Lipoxigenase/biossíntese , Duodeno/metabolismo , Deficiências de Ferro , Distúrbios do Metabolismo do Ferro/metabolismo , Jejuno/metabolismo , Metabolismo dos Lipídeos/genética , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Algoritmos , Animais , Araquidonato 12-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/genética , Western Blotting , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Cromatografia Líquida de Alta Pressão , Análise por Conglomerados , Modelos Animais de Doenças , Duodeno/enzimologia , Duodeno/patologia , Indução Enzimática , Perfilação da Expressão Gênica/métodos , Imuno-Histoquímica , Distúrbios do Metabolismo do Ferro/enzimologia , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/patologia , Jejuno/enzimologia , Jejuno/patologia , Ácidos Linoleicos/metabolismo , Fígado/metabolismo , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase ReversaAssuntos
Neurodegeneração Associada a Pantotenato-Quinase/classificação , Eutanásia/ética , Humanos , Distúrbios do Metabolismo do Ferro/classificação , Distúrbios do Metabolismo do Ferro/enzimologia , Distúrbios do Metabolismo do Ferro/genética , Mutação/genética , Socialismo Nacional , Neurologia/ética , Neurologia/tendências , Neurodegeneração Associada a Pantotenato-Quinase/enzimologia , Neurodegeneração Associada a Pantotenato-Quinase/genética , Publicações Periódicas como Assunto/ética , Publicações Periódicas como Assunto/tendências , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Terminologia como Assunto , Violência/éticaRESUMO
Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal-recessive disorder caused by mutations in the PANK2 gene. The authors report clinical and genetic findings of 16 patients with PKAN. The authors identified 12 mutations in the PANK2 gene, five of which were new. Only nine patients could be classified as classic or atypical PKAN, and intermediate phenotypes are described. Two patients presented with motor tics and obsessive-compulsive behavior suggestive of Tourette syndrome.
Assuntos
Encefalopatias Metabólicas Congênitas/genética , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Mutação/genética , Neurodegeneração Associada a Pantotenato-Quinase/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adolescente , Adulto , Encefalopatias Metabólicas Congênitas/enzimologia , Encefalopatias Metabólicas Congênitas/fisiopatologia , Criança , Coenzima A/biossíntese , Análise Mutacional de DNA , Feminino , Testes Genéticos , Globo Pálido/metabolismo , Globo Pálido/patologia , Globo Pálido/fisiopatologia , Transtornos Heredodegenerativos do Sistema Nervoso/enzimologia , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Humanos , Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/enzimologia , Distúrbios do Metabolismo do Ferro/genética , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Transtornos Mentais/enzimologia , Transtornos Mentais/genética , Transtornos Mentais/fisiopatologia , Pessoa de Meia-Idade , Transtorno Obsessivo-Compulsivo/enzimologia , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/fisiopatologia , Neurodegeneração Associada a Pantotenato-Quinase/enzimologia , Neurodegeneração Associada a Pantotenato-Quinase/fisiopatologia , Fenótipo , Tratos Piramidais/fisiopatologia , Tiques/enzimologia , Tiques/genética , Tiques/fisiopatologiaRESUMO
Aceruloplasminemia is a disorder of iron metabolism caused by mutations in the ceruloplasmin gene. It is characterized by progressive neurodegeneration of the retina, basal ganglia, dentate nucleus and cerebral cortex in association with iron accumulation in these tissues. Enzyme activities in the mitochondrial respiratory chain of the cerebral cortices of two patients were reduced to 62% and 71% for complexes I and IV. Malondialdehyde, a marker of lipid peroxidation, was three times higher than the control value and was accompanied by increased expression of superoxide dismutase 2 (Mn SOD). These findings suggest that iron-mediated free radicals contribute to the impairment of mitochondrial energy metabolism in aceruloplasminemia
