RESUMEN
OBJECTIVE: The apolipoprotein E (APOE) epsilon4 allele is a well-established factor associated with age-related macular degeneration (AMD). This disorder is characterized by a typical progressive central visual impairment. Our aim was to study further the relationship of the APOE genotype associated with AMD. MATERIALS AND METHODS: We evaluated a group of 95 patients with AMD and 65 controls. The APOE genotype for each participant in the study was determined. RESULTS: The allele was associated with age-related macular degeneration (OR = 5.6; 95% CI = 3.4-8.8 ; p < 0.001). Female patients with at least one epsilon4 allele had a significantly earlier age at diagnosis (epsilon4+ = 72.2 S.D. 5.1; epsilon4- = 78.8 +/- 5.7; p < 0.001). CONCLUSIONS: The APOE epsilon4 allele is not a protective factor for AMD, but is associated with an increased risk of its development.
Asunto(s)
Apolipoproteínas E/genética , Degeneración Macular/genética , Factores de Edad , Anciano , Alelos , Apolipoproteína E4 , Estudios de Casos y Controles , ADN/análisis , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Reacción en Cadena de la PolimerasaRESUMEN
A number of neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by intraneuronal accumulation of the tau protein. Some forms of FTDP-17 are caused by mutations in the tau gene affecting exon 10 splicing. Therefore, dysregulation of tau pre-mRNA splicing may be a contributing factor to sporadic tauopathies. To address this question, we devised a real-time RT-PCR strategy based on the use of a single fluorogenic probe to evaluate the ratio between tau isoforms containing or lacking exon 10 (4R/3R ratio) in post-mortem brain samples. We found a two- to six-fold increase in the 4R/3R ratio in cases of FTDP-17 linked to a splice site mutation, hence confirming the validity of the strategy. The difference in the 4R/3R ratio in the superior temporal and superior frontal gyri between AD and control brains was not statistically significant. Similarly, there was no significant difference in the 4R/3R ratio between Pick's disease cases and controls, indicating that the predominance of tau3R protein in PiD reflects post-translational modifications of specific isoforms. This study indicates that post-translational events are likely to be the main factors controlling tau isoform composition in sporadic tauopathies and highlights the benefit of quantitative RT-PCR in the assessment of splicing abnormalities in tauopathies.
Asunto(s)
Empalme Alternativo/genética , Encéfalo/metabolismo , Mutación/genética , Polimorfismo Genético/genética , Tauopatías/genética , Proteínas tau/genética , Anciano , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Secuencia de Bases/genética , Encéfalo/patología , Encéfalo/fisiopatología , Demencia/genética , Demencia/metabolismo , Demencia/fisiopatología , Exones/genética , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Enfermedad de Pick/genética , Enfermedad de Pick/metabolismo , Enfermedad de Pick/fisiopatología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional/genética , Sitios de Empalme de ARN/genética , ARN Mensajero/análisis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Tauopatías/metabolismo , Tauopatías/fisiopatología , Proteínas tau/metabolismoRESUMEN
In transmissible spongiform encephalopathies (TSEs), an altered form of prion protein (PrP), PrPres, aggregates in amyloid fibrils and accumulates in the brain. Several point mutations of the PrP gene have been associated with the TSEs, so, to investigate how the mutations affect the biological activity of PrP, we analyzed the biological effects and chemicophysical characteristics of the peptide homologous to the wild-type and mutated sequence of PrP fragments. The mutation P102L altered the biological activity of PrP 89-106, which became neurotoxic without changing its fibrillogenic capacity. The mutation (D178N) in the PrP 169-185 strongly increased the neurotoxic activity of the native sequence. In this case, there was also a clear alteration of the structural conformation. None of the other mutations considered, including A117V, seemed to influence the biological activities of the respective peptides. These data identify new neurotoxic fragments of PrP in the mutated form and elucidate their genetic influence on the pathogenesis of TSEs.
Asunto(s)
Encefalopatías/genética , Mutación , Enfermedades por Prión/genética , Priones/genética , Secuencia de Aminoácidos , Animales , Encéfalo/patología , Encéfalo/ultraestructura , Encefalopatías/patología , Microscopía Electrónica , Datos de Secuencia Molecular , Enfermedades por Prión/patología , Ratas , Análisis de SecuenciaRESUMEN
Apolipoprotein E (ApoE) genotypes, presenilin 1 (PS-1) and alpha(1)-antichymotrypsin (ACT) polymorphism and the association of the genotypes were examined in patients with Alzheimer's disease (AD, n = 121) or vascular dementia (VD, n = 68) in comparison with elderly controls (n = 125). The frequency of the ApoE epsilon 4 allele was significantly increased both in late-onset AD (0.35) and in VD (0.17); the frequency of ApoE epsilon 2 was significantly reduced in AD, but it was similar in VD and controls. The presence of the allele 1 of PS-1 intronic polymorphism was not associated with AD or VD and was not influenced by the ApoE genotypes. Also, the frequency of allele A of the intronic polymorphism of ACT was similar in AD, VD and controls and it was not altered by ApoE or PS-1 genotypes. The results confirm the association between ApoE epsilon 4 and AD and indicate an increase in ApoE epsilon 4 in Vd, too. A potential protective role of ApoE epsilon 2 is also suggested for late-onset AD but not for VD. No association was shown between ACT allele A and PS-1 allele 1 in AD or VD.
Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteínas E/genética , Demencia Vascular/genética , Proteínas de la Membrana/genética , Polimorfismo Genético/genética , alfa 1-Antitripsina/genética , Anciano , Alelos , Femenino , Genotipo , Humanos , Masculino , Presenilina-1RESUMEN
Objetivo: El alelo e4 de la apoliporoteína E (APOE) es un factor de riesgo bien establecido en la degeneración macular asociada a la edad (DMAE). Esta enfermedad se caracteriza por pérdida progresiva de la visión central. Nuestro objetivo es estudiar la asociación del genotipo APOE con la DMAE.Material y método: Se estudió un grupo de 95 pacientes con DMAE y 65 controles. A todos se les determinó el genotipo de la APOE.Resultados: El alelo epsilon4 se asoció a degeneración macular asociada a la edad (OR = 5,6; 95% CI= 3,4-8,8 ; p< 0,001). La edad de diagnóstico es significativamente inferior en las pacientes que tienen al menos un alelo epsilon4 (epsilon4+ = 72,2 D.E. 5,1; epsilon4- = 78,8 +/- 5,7; p<0,001).Conclusiones: El alelo epsilon4 de la APOE no es un factor de protección para la degeneración macular asociada a la edad y se asocia a un mayor riesgo de desarrollarla
Objective: The apolipoprotein E (APOE) e4 allele is a well-established factor associated with age-related macular degeneration (AMD). This disorder is characterized by a typical progressive central visual impairment. Our aim was to study further the relationship of the APOE genotype associated with AMD. Materials and methods: We evaluated a group of 95 patients with AMD and 65 controls. The APOE genotype for each participant in the study was determined. Results: The allele was associated with age-related macular degeneration (OR = 5.6; 95% CI= 3.4-8.8 ; p< 0.001). Female patients with at least one epsilon4 allele had a significantly earlier age at diagnosis (epsilon4+ = 72.2 S.D. 5.1; epsilon4- = 78.8 ± 5.7; p<0.001). Conclusions: The APOE epsilon4 allele is not a protective factor for AMD, but is associated with an increased risk of its development