Implicación de la síntesis de nucleótidos de pirimidina en la enfermedad de Alzheimer

Pese a que las neuronas son células completamente diferenciadas, sus requerimientos de pirimidinas para producir y mantener la extensa membrana plasmática que compone sus neuritas hacen suponer que la ruta de síntesis de novo de nucleótidos de pirimidina necesita estar activa en el cerebro humano adulto. Esta ruta está conectada con el sistema de fosforilación oxidativa (OXPHOS) a través de la enzima DHODH. Muchos pacientes con enfermedad de Alzheimer (AD) muestran una disfunción OXPHOS muy temprana. Así, los individuos con AD podrían, por tanto, tener afectada la síntesis de nucleótidos de pirimidina y la ruta de salvamento de pirimidinas sería particularmente importante para ellos. Con este trabajo hemos confirmado no solo que la ruta de síntesis de novo de nucleótidos de pirimidina se encuentra en cerebro humano adulto, sino que tanto esta ruta como la de salvamento de pirimidinas están afectadas en los pacientes con AD. Además, usando un modelo celular, hemos confirmado como la disfunción OXPHOS, reduciendo secundariamente la actividad de la ruta de síntesis de novo de nucleótidos de pirimidina, provoca alteraciones en distintas funciones neuronales, que son corregidas por la administración de uridina.La disminución en la actividad de las rutas de síntesis de nucleótidos de pirimidina parece ser un mecanismo fisiopatológico de la AD, secundario a la disfunción OXPHOS, que podría tratarse mediante la administración de uridina.<br /

Efecto del genotipo mitocondrial sobre la composición del plasmalema neuronal, la sinaptogenésis y la enfermedad de Alzheimer

La enfermedad de Alzheimer (AD) se define como un proceso neurodegenerativo del sistema nervioso central (CNS). Esta patología se caracteriza por la pérdida de memoria, cambios de comportamiento y confusión, dejando a los pacientes completamente inválidos. Este tipo de procesos mentales dependen del correcto funcionamiento de las redes neuronales. En el caso del AD son las neuronas colinérgicas las que se ven afectadas. Las conexiones neuronales vienen dadas por la correcta sinaptogénesis, y para ello necesitan la producción de neuritas, elongaciones de la membrana plásmatica de la propia célula. Los principales compuestos de la membrana celular son los fosfátidos. Este tipo de molécula necesita para su formación la participación del sistema de fosforilación oxidativa (OXPHOS) y la enzima dihidroorotato deshidrogenasa (DHODH). La combinación de ambos factores da lugar al nucleósido de pirimidina, uridina, precursor de los fosfátidos. Un fallo en la cadena respiratoria de la mitocondria produciría como consecuencia el de la DHODH y una disminución de los niveles de uridina celulares. Se ha observado en diferentes estudios que la administración de uridina y compuestos relacionados (CDP-colina, CTP, UTP) producían una mejoría en pacientes de AD. El estudio de la inhibición de estos dos factores, el sistema OXPHOS y la DHODH, podría explicar el papel de la mitocondria en la formación de la membrana celular y las conexiones neuronales que se ven dañadas con la AD

Efecto de la inhibición del sistema de fosforilación oxidativa sobre la diferenciación neuronal en la enfermedad de Alzheimer

La enfermedad de Alzheimer es un síndrome neurodegenerativo progresivo del sistema nervioso central caracterizado principalmente por deterioro cognitivo y pérdida de memoria. De acuerdo a la hipótesis de cascada mitocondrial, se ha propuesto que la causa de esta patología podría ser el declive de la funcionalidad del sistema de fosforilación oxidativa mitocondrial, responsable de la generación de energía en las células e implicado en la diferenciación neuronal. Puesto que este declive puede estar acrecentado por factores ambientales, se ha estudiado el efecto que tiene el cloruro de tributilestaño, un xenobiótico ambiental que inhibe el sistema de fosforilación oxidativa, sobre la diferenciación neuronal. El estudio del efecto de concentraciones inhibitorias de la función mitocondrial de este xenobiótico se ha realizado en células SH-SY5Y, modelos celulares de enfermedad de Alzheimer ampliamente utilizados en investigación, durante procesos de diferenciación a neurona colinérgica y dopaminérgica. Concentraciones crecientes de tributilestaño disminuyen la respiración mitocondrial y parecen ser citotóxicas para la línea celular cuando se encuentra sometida a tratamiento con ácido retinoico, un agente inductor de la diferenciación. El análisis morfológico y del marcador neuronal beta-III-tubulina muestran que la exposición a 50 nM de tributilestaño impide la diferenciación neuronal en todos los casos estudiados, mientras que 25 nM impide únicamente la diferenciación colinérgica

Modificaciones de los tRNAs Mitocondriales y Enfermedades por Mutaciones en el mtDNA

Meta-análisis de los mt-tRNAs humanos para estudiar si existe una relación entre las mutaciones localizadas en las bases que se encuentras modificadas en su estado fisiológico y el padecimiento de ciertas patologías con el objetivo de, en caso de probarse esta hipótesis cierta, poder establecer un criterio más concreto para poder diagnosticar estas enfermedades de forma rápida y efectiva.<br /

Uridine Prevents Negative Effects of OXPHOS Xenobiotics on Dopaminergic Neuronal Differentiation

Neuronal differentiation appears to be dependent on oxidative phosphorylation capacity. Several drugs inhibit oxidative phosphorylation and might be detrimental for neuronal differentiation. Some pregnant women take these medications during their first weeks of gestation when fetal nervous system is being developed. These treatments might have later negative consequences on the offspring’s health. To analyze a potential negative effect of three widely used medications, we studied in vitro dopaminergic neuronal differentiation of cells exposed to pharmacologic concentrations of azidothymidine for acquired immune deficiency syndrome; linezolid for multidrug-resistant tuberculosis; and atovaquone for malaria. We also analyzed the dopaminergic neuronal differentiation in brains of fetuses from pregnant mice exposed to linezolid. The drugs reduced the in vitro oxidative phosphorylation capacity and dopaminergic neuronal differentiation. This differentiation process does not appear to be affected in the prenatally exposed fetus brain. Nevertheless, the global DNA methylation in fetal brain was significantly altered, perhaps linking an early exposure to a negative effect in older life. Uridine was able to prevent the negative effects on in vitro dopaminergic neuronal differentiation and on in vivo global DNA methylation. Uridine could be used as a protective agent against oxidative phosphorylation-inhibiting pharmaceuticals provided during pregnancy when dopaminergic neuronal differentiation is taking place

Brain pyrimidine nucleotide synthesis and Alzheimer disease

Many patients suffering late-onset Alzheimer disease show a deficit in respiratory complex IV activity. The de novo pyrimidine biosynthesis pathway connects with the mitochondrial respiratory chain upstream from respiratory complex IV. We hypothesized that these patients would have decreased pyrimidine nucleotide levels. Then, different cell processes for which these compounds are essential, such as neuronal membrane generation and maintenance and synapses production, would be compromised. Using a cell model, we show that inhibiting oxidative phosphorylation function reduces neuronal differentiation. Linking these processes to pyrimidine nucleotides, uridine treatment recovers neuronal differentiation. To unmask the importance of these pathways in Alzheimer disease, we firstly confirm the existence of the de novo pyrimidine biosynthesis pathway in adult human brain. Then, we report altered mRNA levels for genes from both de novo pyrimidine biosynthesis and pyrimidine salvage pathways in brain from patients with Alzheimer disease. Thus, uridine supplementation might be used as a therapy for those Alzheimer disease patients with low respiratory complex IV activity

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Mechanisms and Therapeutic Effects of Benzoquinone Ring Analogs in Primary CoQ Deficiencies

Coenzyme Q (CoQ) is a conserved polyprenylated lipid composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. CoQ biosynthesis involves multiple steps, including multiple modifications of the precursor ring 4-hydroxybenzoic acid. Mutations in the enzymes involved in CoQ biosynthesis pathway result in primary coenzyme Q deficiencies, mitochondrial disorders whose clinical heterogenicity reflects the multiple biological function of CoQ. Patients with these disorders do not always respond to CoQ supplementation, and CoQ analogs have not been successful as alternative approaches. Progress made in understanding the CoQ biosynthesis pathway and studies of supplementation with 4-hydroxybenzoic acid ring analogs have opened a new area in the field of primary CoQ deficiencies treatment. Here, we will review these studies, focusing on efficacy of the different 4-hydroxybenzoic acid ring analogs, models in which they have been tested, and their mechanisms of action. Understanding how these compounds ameliorate biochemical, molecular, and/or clinical phenotypes of CoQ deficiencies is important to develop the most rational treatment for CoQ deficient patients, depending on their molecular defects

Mechanisms and Therapeutic Effects of Benzoquinone Ring Analogs in Primary CoQ Deficiencies

Coenzyme Q (CoQ) is a conserved polyprenylated lipid composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. CoQ biosynthesis involves multiple steps, including multiple modifications of the precursor ring 4-hydroxybenzoic acid. Mutations in the enzymes involved in CoQ biosynthesis pathway result in primary coenzyme Q deficiencies, mitochondrial disorders whose clinical heterogenicity reflects the multiple biological function of CoQ. Patients with these disorders do not always respond to CoQ supplementation, and CoQ analogs have not been successful as alternative approaches. Progress made in understanding the CoQ biosynthesis pathway and studies of supplementation with 4-hydroxybenzoic acid ring analogs have opened a new area in the field of primary CoQ deficiencies treatment. Here, we will review these studies, focusing on efficacy of the different 4-hydroxybenzoic acid ring analogs, models in which they have been tested, and their mechanisms of action. Understanding how these compounds ameliorate biochemical, molecular, and/or clinical phenotypes of CoQ deficiencies is important to develop the most rational treatment for CoQ deficient patients, depending on their molecular defects

The Spanish version of Face-Name Associative Memory Exam (S-FNAME) performance is related to amyloid burden in Subjective Cognitive Decline

The Face-Name Associative Memory Exam (FNAME) is a paired associative memory test created to detect memory deficits in individuals with preclinical Alzheimer’s disease (AD). Worse performance on FNAME in cognitively healthy individuals were found related to higher amyloid beta (Aβ) burden measured with Positron-Emission-Tomography using 11C-PiB (PiB-PET). We previously reported normative data of a Spanish version of FNAME (S-FNAME) in cognitively healthy Spanish-speaking subjects. The aim of the present study was to determine whether performance on S-FNAME was associated with Aβ burden in subjective cognitive decline (SCD) individuals. 200 SCD subjects received neurological and neuropsychological assessments, including the S-FNAME and the Word List task from the Wechsler-Memory-Scale-III (WMS-III). Moreover, they received an MRI and (18)F-Florbetaben Positron-Emission-Tomography (FBB-PET) to measure Aβ burden. Three cognitive factor composites were derived for the episodic memory measures (face-name [SFN-N], face-occupation [SFN-O] and WMS-III) to determine whether episodic memory performance was related to Aβ deposition. Higher global Aβ deposition was significantly related to worse performance on SFN-N but not with SFN-O or WMS-III Composite. Moreover, worse SFN-N performance was significantly related to higher Aβ deposition in bilateral Posterior Cingulate Cortex. The S-FNAME may be a promising neuropsychological tool for detecting SCD individuals with preclinical AD