Pathophysiological Role of Purines and Pyrimidines in Neurodevelopment: Unveiling New Pharmacological Approaches to Congenital Brain Diseases

Abstract

In recent years, a substantial body of evidence has emerged demonstrating that purine and pyrimidine synthesis and metabolism play major roles in controlling embryonic and fetal development and organogenesis. Dynamic and time-dependent changes in the expression of purine metabolizing enzymes (such as ectonucleotidases and adenosine deaminase) represent a key checkpoint for the correct sequential generation of the different signaling molecules, that in turn activate their specific membrane receptors. In neurodevelopment, Ca2+ release from radial glia mediated by P2Y1 purinergic receptors is fundamental to allow neuroblast migration along radial glia processes, and their correct positioning in the different layers of the developing neocortex. Moreover, ATP is involved in the development of synaptic transmission and contributes to the establishment of functional neuronal networks in the developing brain. Additionally, several purinergic receptors (spanning from adenosine to P2X and P2Y receptor subtypes) are differentially expressed by neural stem cells, depending on their maturation stage, and their activation tightly regulates cell proliferation and differentiation to either neurons or glial cells, as well as their correct colonization of the developing telencephalon. The purinergic control of neurodevelopment is not limited to prenatal life, but is maintained in postnatal life, when it plays fundamental roles in controlling oligodendrocyte maturation from precursors and their terminal differentiation to fully myelinating cells. Based on the above-mentioned and other literature evidence, it is now increasingly clear that any defect altering the tight regulation of purinergic transmission and of purine and pyrimidine metabolism during pre- and post-natal brain development may translate into functional deficits, which could be at the basis of severe pathologies characterized by mental retardation or other disturbances. This can occur either at the level of the recruitment and/or signaling of specific nucleotide or nucleoside receptors or through genetic alterations in key steps of the purine salvage pathway. In this review, we have provided a critical analysis of what is currently known on the pathophysiological role of purines and pyrimidines during brain development with the aim of unveiling new future strategies for pharmacological intervention in different neurodevelopmental disorders.

Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

“…Many enzymatic defects involve brain development by intricated mechanisms. 18 Metabolite repair defects are a new growing category in which symptoms are linked to the accumulation of a toxic compound like in L-2-hydroxyglutaric aciduria, 19 or NAXE mutations-NAXE catalyzes the epimerization of NAD(P)HX, thereby avoiding the accumulation of toxic metabolites. 20 Vitamins (transport, and intracellular processing) interfere with many different metabolic pathways where they act as enzymatic cofactors, chaperones or signaling molecules.…”

Reduced purine biosynthesis in humans after their divergence from Neandertals

“…In general, it is interesting that although ADSL is expressed and functions in all tissues, the down-regulation of purine biosynthesis in humans relative to apes, and in humanized mice relative to wild-type mice, is most pronounced in the brain. It is also interesting that mutations in humans that affect enzymes involved in purine metabolism have more pathological consequences in the nervous system than in other organs (Fumagalli et al, 2017;Micheli et al, 2011). It is thus possible that the A429V substitution in ADSL has contributed to human-specific changes in brain development and function.…”

Guanosine-Based Nucleotides, the Sons of a Lesser God in the Purinergic Signal Scenario of Excitable Tissues

“…Purinergic control of neural development is not limited to early phases of prenatal life, but is also maintained later when it plays a fundamental role in controlling the maturation of glial components such as oligodendrocytes [14]. When brain development is complete, some purinergic mechanisms could be silenced, but could be re-activated in adult brain after injury, suggesting a role for purines in regeneration and self-repair [15,16].…”