Show Me Your Friends and I Tell You Who You Are: The Many Facets of Prion Protein in Stroke

Abstract

<jats:p>Ischemic stroke belongs to the leading causes of mortality and disability worldwide. Although treatments for the acute phase of stroke are available, not all patients are eligible. There is a need to search for therapeutic options to promote neurological recovery after stroke. The cellular prion protein (PrPC) has been consistently linked to a neuroprotective role after ischemic damage: it is upregulated in the penumbra area following stroke in humans, and animal models of stroke have shown that lack of PrPC aggravates the ischemic damage and lessens the functional outcome. Mechanistically, these effects can be linked to numerous functions attributed to PrPC: (1) as a signaling partner of the PI3K/Akt and MAPK pathways, (2) as a regulator of glutamate receptors, and (3) promoting stem cell homing mechanisms, leading to angio- and neurogenesis. PrPC can be cleaved at different sites and the proteolytic fragments can account for the manifold functions. Moreover, PrPC is present on extracellular vesicles (EVs), released membrane particles originating from all types of cells that have drawn attention as potential therapeutic tools in stroke and many other diseases. Thus, identification of the many mechanisms underlying PrPC-induced neuroprotection will not only provide further understanding of the physiological functions of PrPC but also new ideas for possible treatment options after ischemic stroke.</jats:p>

Prion Protein: The Molecule of Many Forms and Faces

“…PrP-knockout animal models subject to ischemia showed intensive ischemic damage and a reduced chance of regeneration whereas the possibility of PrP C synthesis resulted in PrP C overexpression and decreased ischemic damage [127]. Studies on ischemic strokes have indicated that PrP C overexpression can reduce the lesion size compared with wild-type mice, ascribing PrP C a protective role in ischemia damage [129][130][131][132][133][134][135]. After an ischemic insult, PrP C is associated with neuroprotective and regenerative processes by interacting with various cytosolic and transmembrane signal proteins.…”

Copper as a Collaborative Partner of Zinc-Induced Neurotoxicity in the Pathogenesis of Vascular Dementia

“…AβPs reportedly inhibit the binding of Cu 2+ to PrP C [ 82 ]. PrP C contributes to AD pathogenesis as a toxic receptor of AβP oligomers [ 83 ]. Moreover, recent studies have suggested the involvement of PrP C in ischemia-induced neurotoxicity [ 84 , 85 ].…”

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.…”

“…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).…”