Brain pyrimidine nucleotide synthesis and Alzheimer disease

Pesini, Alba ; Iglesias, Eldris (Universidad de Zaragoza) ; Bayona-Bafaluy, M Pilar (Universidad de Zaragoza) ; Garrido-Pérez, Nuria (Universidad de Zaragoza) ; Meade, Patricia (Universidad de Zaragoza) ; Gaudó, Paula (Universidad de Zaragoza) ; Jiménez-Salvador, Irene (Universidad de Zaragoza) ; Andrés-Benito, Pol ; Montoya, Julio (Universidad de Zaragoza) ; Ferrer, Isidro ; Pesini, Pedro ; Ruiz-Pesini, Eduardo (Universidad de Zaragoza)

Resumen: 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.

Idioma: Inglés

DOI: 10.18632/aging.102328

Año: 2019

Publicado en: AGING-US 11, 19 (2019), 8433-8462
ISSN: 1945-4589

Factor impacto JCR: 4.831 (2019)

Categ. JCR: GERIATRICS & GERONTOLOGY rank: 7 / 51 = 0.137 (2019) - Q1 - T1
Categ. JCR: CELL BIOLOGY rank: 62 / 195 = 0.318 (2019) - Q2 - T1

Factor impacto SCIMAGO: 1.993 - Cell Biology (Q1) - Aging (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/B33-17R
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI17-00021
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI17-00166

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)