Purine nucleoside phosphorylase deficiency induces p53-mediated intrinsic apoptosis in human induced pluripotent stem cell-derived neurons.

Abstract

Purine nucleoside phosphorylase (PNP) is an important enzyme in the purine degradation and salvage pathway. PNP deficiency results in marked T lineage lymphopenia and severe immunodeficiency. Additionally, PNP-deficient patients and mice suffer from diverse non-infectious neurological abnormalities of unknown etiology. To further investigate the cause for these neurologic abnormalities, induced pluripotent stem cells (iPSC) from two PNP-deficient patients were differentiated into neurons. The iPSC-derived PNP-deficient neurons had significantly reduced soma and nuclei volumes. The PNP-deficient neurons demonstrated increased spontaneous and staurosporine-induced apoptosis, measured by cleaved caspase-3 expression, together with decreased mitochondrial membrane potential and increased cleaved caspase-9 expression, indicative of enhanced intrinsic apoptosis. Greater expression of tumor protein p53 was also observed in these neurons, and inhibition of p53 using pifithrin-α prevented the apoptosis. Importantly, treatment of the iPSC-derived PNP-deficient neurons with exogenous PNP enzyme alleviated the apoptosis. Inhibition of ribonucleotide reductase (RNR) in iPSC derived from PNP-proficient neurons with hydroxyurea or with nicotinamide and trichostatin A increased the intrinsic neuronal apoptosis, implicating RNR dysfunction as the potential mechanism for the damage caused by PNP deficiency. The findings presented here establish a potential mechanism for the neurological defects observed in PNP-deficient patients and reinforce the critical role that PNP has for neuronal viability.

• Authors: Michael Tsui, Jeremy Biro, Jonathan Chan, Weixian Min, Kerry Dobbs, Luigi D Notarangelo, Eyal Grunebaum
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 9084 (05 31 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35641516 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Intramural)
• Copyright: © 2022. The Author(s).

Chemical References

• Tumor Suppressor Protein p53
• Purine-Nucleoside Phosphorylase

Topics

• Apoptosis
• Humans
• Induced Pluripotent Stem Cells (cytology)
• Neurons (cytology)
• Primary Immunodeficiency Diseases
• Purine-Nucleoside Phosphorylase (deficiency, metabolism)
• Purine-Pyrimidine Metabolism, Inborn Errors
• Tumor Suppressor Protein p53 (genetics)