Cellular prion protein co‐localizes with nAChR β4 subunit in brain and gastrointestinal tract

Abstract

PrP(C), the cellular isoform of prion protein, is widely expressed in most tissues, including brain, muscle and gastrointestinal tract. Despite its involvement in several bioprocesses, PrP has still no apparent physiological role. During propagation of transmissible spongiform encephalopathies (TSE), prion protein is converted to the pathological isoform, PrP(Sc), in a process believed to be mediated by unknown host factors. The identification of proteins associated with PrP may provide information about both the biology of prions and the pathogenesis of TSE. Thus far, PrP(C) has been shown to interact with synaptic proteins, components of the cytoskeleton and intracellular proteins involved in signalling pathways. Here, we describe the association of PrP with the beta4 subunit of nicotinic acetylcholine receptor (nAChR), as indicated by co-immunoprecipitation assays and double-label immunofluorescence. The interaction between prion protein and native beta4 subunit was further studied by affinity chromatography, using immobilized and refolded recombinant PrP as a bait and brain homogenates from normal individuals. Additionally, the participation of beta4 subunit in the pathogenesis of TSE was studied by in vivo assays. beta4(-/-) and wild-type mice were challenged with the RML (Rocky Mountain Laboratories) infectious agent. Transgenic animals displayed altered incubation times but the deletion of beta4 subunit did not result in a significant change of the incubation period of the disease. Our results suggest that PrP(C) is a member of a multiprotein membrane complex participating in the formation and function of alpha3beta4 nAChR.

Na+/K+-ATPase Is Present in Scrapie-Associated Fibrils, Modulates PrP Misfolding In Vitro and Links PrP Function and Dysfunction

“…Various groups have shown interactions between Na + /K + -ATPase and PrP C [8], [9], [42] and there have been several suggestions that the two proteins associate to form a multiprotein complex with additional partners. One such partner is suggested to be 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP1) [69] and interestingly this protein was identified in one of our SAF preparations and was also detected in another below the level of confidence. CNP1 is a membrane bound enzyme involved in the synthesis of the myelin sheath [70] and it has been reported that CNP1 may act as an anchor for tubulin [71].…”

A Mutant Prion Protein Sensitizes Neurons to Glutamate-Induced Excitotoxicity

“…These results suggest that ΔCR PrP, instead of silencing NMDA receptors like WT PrP, activates them, possibly via a physical interaction with NR2D or other channel subunits. Alternatively, ΔCR PrP could also directly or indirectly affect the activity of other ion channels, such as nAChRs (Petrakis et al, 2008; Beraldo et al, 2010), to increase neuronal excitability. A number of electrophysiological abnormalities have been reported in neurons from PrP knock-out mice (Linden et al, 2008), suggesting that PrP C might normally modulate several kinds of ion channels, a function that could be corrupted by ΔCR or other central region mutations.…”

Role of α7 Nicotinic Acetylcholine Receptor in Calcium Signaling Induced by Prion Protein Interaction with Stress-inducible Protein 1

“…Recent data demonstrated that PrP C is co-localized with the ␤4 subunit of nAChR in the brain and gastrointestinal tract. However, infection experiments using the Rocky Mountain Laboratory prion strain in ␤4nAChR knock-out mice demonstrated that these animals presented with the same disease incubation period when compared with controls (61).…”