The cellular prion protein PrP^C is highly expressed in neurons, but also present in non-neuronal tissues, including the testicles and spermatozoa. Most immune cells and their bone marrow precursors also express PrP^C. Clearly, this protein operates in highly diverse cellular contexts. Investigations into putative stress-protective roles for PrP^C have resulted in an array of functions, such as inhibition of apoptosis, stimulation of anti-oxidant enzymes, scavenging roles, and a role in nuclear DNA repair. We have studied stress resilience of spermatozoa and peripheral blood mononuclear cells (PBMCs) derived from non-transgenic goats that lack PrP^C (PRNP^Ter/Ter) compared with cells from normal (PRNP^+/+) goats. Spermatozoa were analyzed for freeze tolerance, DNA integrity, viability, motility, ATP levels, and acrosome intactness at rest and after acute stress, induced by Cu²⁺ ions, as well as levels of reactive oxygen species (ROS) after exposure to FeSO₄ and H₂O₂. Surprisingly, PrP^C-negative spermatozoa reacted similarly to normal spermatozoa in all read-outs. Moreover, in vitro exposure of PBMCs to Doxorubicin, H₂O₂ and methyl methanesulfonate (MMS), revealed no effect of PrP^C on cellular survival or global accumulation of DNA damage. Similar results were obtained with human neuroblastoma (SH-SY5Y) cell lines stably expressing varying levels of PrP^C. RNA sequencing of PBMCs (n = 8 of PRNP^+/+ and PRNP^Ter/Ter) showed that basal level expression of genes encoding DNA repair enzymes, ROS scavenging, and antioxidant enzymes were unaffected by the absence of PrP^C. Data presented here questions the in vitro cytoprotective roles previously attributed to PrP^C, although not excluding such functions in other cell types or tissues during inflammatory stress.

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