Cellular Prion Protein (PrPc): Putative Interacting Partners and Consequences of the Interaction

Abstract

Cellular prion protein (PrPc) is a small glycosylphosphatidylinositol (GPI) anchored protein most abundantly found in the outer leaflet of the plasma membrane (PM) in the central nervous system (CNS). PrPc misfolding causes neurodegenerative prion diseases in the CNS. PrPc interacts with a wide range of protein partners because of the intrinsically disordered nature of the protein’s N-terminus. Numerous studies have attempted to decipher the physiological role of the prion protein by searching for proteins which interact with PrPc. Biochemical characteristics and biological functions both appear to be affected by interacting protein partners. The key challenge in identifying a potential interacting partner is to demonstrate that binding to a specific ligand is necessary for cellular physiological function or malfunction. In this review, we have summarized the intracellular and extracellular interacting partners of PrPc and potential consequences of their binding. We also briefly describe prion disease-related mutations at the end of this review.

Concussion/Mild Traumatic Brain Injury (TBI) Induces Brain Insulin Resistance: A Positron Emission Tomography (PET) Scanning Study

“…Repeated mild TBI causes brain IR and dysregulation of glucose metabolism; partly this may be due to the dislodgment of PrPc. An interaction between the lipid raft localized flotillin and CAP (a key marker in the secondary insulin signaling pathway) has been demonstrated [33,34], and flotillin also interacts with PrPc [35,36]. In the present study, we investigated the molecular link between PrPc and brain insulin resistance (CAP/Cbl/TC10 pathway) in a single and repeated mild TBI-induced mouse model.…”

The cellular prion protein interacts with and promotes the activity of Na,K-ATPases

“…Therefore, considerable efforts have been invested in both the characterization of the membrane microdomain in which PrP C resides and the identification of its interactions. Although no shortage of PrP C binders have been described [ 8 ], this body of literature is somewhat fragmented and inconsistent. To shed light on whether differences in methodology or experimental paradigms are to blame, we recently undertook the first side-by-side analysis of proteins that were in vivo crosslinked to PrP C in four distinct mouse cell models using identical workflows [ 9 ].…”

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

“…PRPC is expressed in neurons and glia, mainly on the cell surface as a glycosylphosphatidylinositol-anchored protein localized to lipid rafts. Though PRPC was, and understandably so, initially viewed as a bête noire, it is becoming clear that it serves many important physiological functions by interacting with extracellular and intracellular partners (Table 3) (Aguzzi et al, 2008;Castle and Gill, 2017;Didonna, 2013;Gavin et al, 2020;Linden, 2017;Miranzadeh Mahabadi and Taghibiglou, 2020;Peggion et al, 2017;Puig et al, 2020;Schneider et al, 2011;Sorgato et al, 2009;Watts et al, 2018;Wulf et al, 2017). Importantly, unlike APP, PRPC does not possess an intracytoplasmic tail and appears to act as a co-receptor serving as a conduit for various extracellular and membrane molecules.…”

“…This process is blockable by allosteric modulators of mGluR5 which when administered to AD model mice, abrogate decreased synaptic density and memory deficits (Haas et al, 2014;Hamilton et al, 2016;Um et al, 2013) and restore LTP impairments induced by oAβ42 (Rammes et al, 2011). Studies to date have generally interpreted these effects in the light of neurotoxicity (see Jarosz-Griffiths et al, 2016;Lima-Filho and Oliveira, 2018;Miranzadeh Mahabadi and Taghibiglou, 2020;Nygaard and Strittmatter, 2009;Peggion et al, 2017;Purro et al, 2018;Watts et al, 2018;Zhang et al, 2019b). However, under non-diseased physiological conditions where endogenous Aβ42 levels are lower, the PRPC-mGluR5 complex may be a substrate through which Aβ42 and other molecules act to maintain, limit and protect established neuroplasticity from modification by continued excitatory synaptic input.…”

“…See table of abbreviations for explanation of abbreviations. (See Aguzzi et al, 2008;Castle and Gill, 2017;Didonna, 2013;Liebert et al, 2014;Linden, 2017;Miranzadeh Mahabadi and Taghibiglou, 2020;Puig et al, 2020;Sorgato et al, 2009;Steinert, 2015;Watts et al, 2018;Wulf et al, 2017). Modulates NF-κB (NF-κB implicated in adult neurogenesis and structural plasticity).…”