Cellular prion protein electron microscopy: attempts/limits and clues to a synaptic trait. Implications in neurodegeneration process

Abstract

Prion diseases are caused by an infectious agent constituted by a rogue protein called prion (PrP Sc) of neuronal origin (PrP c) and are exemplified by Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in cattle. Considerable efforts have been made to understand the cerebral damage caused by these diseases but a clear comprehensive view cannot be achieved without defining the neurophysiological function of PrP c. This lack of information is in part attributable to our ignorance of the precise localization of PrP c in the brain neuronal cell. One relevant option to explore this aspect is to undertake PrP immunohistochemistry at the electron-microscopy level, knowing that this challenge raises major technical constraints. In describing the attempts and restrictions of the various approaches used, we review here the efforts that have been invested in this particular field of prionology. The common result emerging from these contributions is that the synapse could be the site at which PrP c exerts its critical activity. This location suggests, in the perspective of synaptic regulation, that PrP c can be assigned multiple biological functions and supports the novel concept that prion-like changes are involved in long-term memory formation. The synaptic trait of PrP c and PrP Sc suggests that synapse loss is the key event in neuronal death. Interestingly, synaptic alterations are also considered to be predominant in the pathophysiological mechanism in Alzheimer, Parkinson and Huntington diseases. All these brain disorders, characterized by the formation of a specific amyloid protein of synaptic origin, can be classified under the heading of amyloidogenic synaptopathies.

Cyclin-dependent Kinase 5 Phosphorylation of Familial Prion Protein Mutants Exacerbates Conversion into Amyloid Structure

“…Furthermore, the phosphorylated WT PrP did not have the ability to seed PrP conversion in a homologous reaction over a period of 60 h. Lastly, the phosphorylation at Ser 43 of PrP has been detected in normal adult mouse brain synaptic membranes (18). Interestingly, PrP is localized at the synapse, and synaptic membrane preparations support conversion of PrP in vitro (48,49). Cdk5 is also localized in presynaptic and postsynaptic compartments and is involved in numerous pathways that are implicated in synaptic plasticity and function, including memory (50).…”

Physiological role of prions in regulation of Ca2+-transport and neurodegenerative diseases

“…Крім того, фізіологіч-ний пріон бере участь у формуванні синаптичної структури та її функціонуванні [32], оскільки дисфункція синапсів є основною молекулярною патологією за прі-онних інфекцій [2,22].…”

“…6, 1) [32]. Згодом, щоб набути функціональної активності, він специфічно Іони Купруму здатні селективно зв'язуватися октапептидними повторами PrP C і є фактором ендоцитозу, особливо в поєднанні з лігандами (LRP 1 ) [32].…”

“…PrP C бере участь у нейротрансмісії (рис. 6, 4), взаємодіючи з синапсином 1 і си-нап тофізином, які беруть участь у процесі екзо-ендоцитотичного циклу синаптич-них міхурців [32]. Така мембрано-незв'язана форма PrP C (5) була виявлена у закінченнях аксонів за допомогою імунологічних методів [22].…”

Alternative Translation Initiation Generates Cytoplasmic Sheep Prion Protein

“…The flexibility observed in the subcellular localization of PrP C has been suggested to be a requirement for normal functions of the protein (14,19,20), but how cytoplasmic and nuclear variants arise has not been established. Cytoplasmic PrP could be a result of retro-translocation from the endoplasmic reticulum (ER), as part of an unfolded protein response (21)(22)(23) or from attenuated ER import of PrP under conditions of lumenal stress in the ER (24,25).…”