Nucleotide Salvage Deficiencies, DNA Damage and Neurodegeneration

Abstract

Nucleotide balance is critically important not only in replicating cells but also in quiescent cells. This is especially true in the nervous system, where there is a high demand for adenosine triphosphate (ATP) produced from mitochondria. Mitochondria are particularly prone to oxidative stress-associated DNA damage because nucleotide imbalance can lead to mitochondrial depletion due to low replication fidelity. Failure to maintain nucleotide balance due to genetic defects can result in infantile death; however there is great variability in clinical presentation for particular diseases. This review compares genetic diseases that result from defects in specific nucleotide salvage enzymes and a signaling kinase that activates nucleotide salvage after DNA damage exposure. These diseases include Lesch-Nyhan syndrome, mitochondrial depletion syndromes, and ataxia telangiectasia. Although treatment options are available to palliate symptoms of these diseases, there is no cure. The conclusions drawn from this review include the critical role of guanine nucleotides in preventing neurodegeneration, the limitations of animals as disease models, and the need to further understand nucleotide imbalances in treatment regimens. Such knowledge will hopefully guide future studies into clinical therapies for genetic diseases.

A Plasma Metabolomic Signature Involving Purine Metabolism in Human Optic Atrophy 1 (OPA1)-Related Disorders

“…pools, is well established in patients carrying mutations in the thymidine kinase, thymidine phosphorylase, and deoxyguanosine kinase genes. 36,37 Despite the heterogeneity of this disease and the small size of the cohort, a robust metabolomics signature has been obtained. One limitation of our metabolomics analysis on plasma, while interesting in the sense that it gives a general view of the individual's conditions, is in fact not suitable to identify the organs that are responsible of the compounds' secretion contributing to the signature.…”

How Excessive cGMP Impacts Metabolic Proteins in Retinas at the Onset of Degeneration

“…Recent studies have shown that disruption of mitochondrial energy metabolism can cause an imbalance of ribonucleotides, which then contributes to neurodegeneration (Fasullo and Endres 2015; Nikkanen et al 2016). Deficient mitochondrial energy production makes Drosophila photoreceptors more vulnerable to light-induced degeneration and produces a visual defect in zebrafish (Taylor et al 2004; Jaiswal et al 2015).…”

Purinergic Signalling and Neurological Diseases: An Update

“…A recent review focuses on the supportive and detrimental roles of P2Y receptors in neurodegeneration [18]. Another review considers nucleotide salvage deficiencies and DNA damage in neurodegenerative diseases [19]. A third review focuses on the neuromodulatory actions mediated by P2X…”