Abstract
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.
Highlights
Late-onset Alzheimer disease (AD) is a chronic and progressive neurodegenerative disorder clinically characterized by memory loss and cognitive decline
Expression of enzymes from pathways for pyrimidine nucleotide synthesis in neurons differentiated from neuroblastoma SH-SY5Y cells To check a potential effect of the oxidative phosphorylation (OXPHOS) dysfunction on neuronal pyrimidine nucleotide synthesis, we used the human neuroblastoma SH-SY5Y cell line as a model
This compound transfers GlcNAc to different proteins, such as transcription factors or histones, which implicates this modification in transcriptional regulation [33, 34]. This is the way uridine recovers TUBB3 and tyrosine hydroxylase (TH) expression. All these results indicate that OXPHOS dysfunction affects de novo pyrimidine nucleotide biosynthesis pathway and has negative consequences on neurons generated from neuroblastoma SH-SY5Y cells
Summary
Late-onset Alzheimer disease (AD) is a chronic and progressive neurodegenerative disorder clinically characterized by memory loss and cognitive decline. It had been previously shown that KCN abolished DHO-induced oxygen consumption in mouse cells and mitochondria from different rat tissues [16, 24], confirming that OXPHOS CIV inhibition affected the de novo pyrimidine biosynthesis pathway.
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