Post-translational modifications in prion diseases

Abstract

More than 650 reversible and irreversible post-translational modifications (PTMs) of proteins have been listed so far. Canonical PTMs of proteins consist of the covalent addition of functional or chemical groups on target backbone amino-acids or the cleavage of the protein itself, giving rise to modified proteins with specific properties in terms of stability, solubility, cell distribution, activity, or interactions with other biomolecules. PTMs of protein contribute to cell homeostatic processes, enabling basal cell functions, allowing the cell to respond and adapt to variations of its environment, and globally maintaining the constancy of the milieu interieur (the body's inner environment) to sustain human health. Abnormal protein PTMs are, however, associated with several disease states, such as cancers, metabolic disorders, or neurodegenerative diseases. Abnormal PTMs alter the functional properties of the protein or even cause a loss of protein function. One example of dramatic PTMs concerns the cellular prion protein (PrP^C), a GPI-anchored signaling molecule at the plasma membrane, whose irreversible post-translational conformational conversion (PTCC) into pathogenic prions (PrP^Sc) provokes neurodegeneration. PrP^C PTCC into PrP^Sc is an additional type of PTM that affects the tridimensional structure and physiological function of PrP^C and generates a protein conformer with neurotoxic properties. PrP^C PTCC into PrP^Sc in neurons is the first step of a deleterious sequence of events at the root of a group of neurodegenerative disorders affecting both humans (Creutzfeldt-Jakob diseases for the most representative diseases) and animals (scrapie in sheep, bovine spongiform encephalopathy in cow, and chronic wasting disease in elk and deer). There are currently no therapies to block PrP^C PTCC into PrP^Sc and stop neurodegeneration in prion diseases. Here, we review known PrP^C PTMs that influence PrP^C conversion into PrP^Sc. We summarized how PrP^C PTCC into PrP^Sc impacts the PrP^C interactome at the plasma membrane and the downstream intracellular controlled protein effectors, whose abnormal activation or trafficking caused by altered PTMs promotes neurodegeneration. We discussed these effectors as candidate drug targets for prion diseases and possibly other neurodegenerative diseases.

Keywords: PDK1 (PDPK1); PDK4; ROCK; neurodegenerative diseases; phosphorylation; sialylation; signaling; α-Secretases.

Figure 1

PrP^C PTMs influence the post-translational conformational conversion of PrP^C into PrP^Sc and determine features of prion diseases. Schematic representations of (i) PrP^C structure showing PrP^C PTMs (glycosylation, sialylation, disulfide bond, GPI anchoring, and α-cleavage) and (ii) PrP^C isoforms (non, mono, or biglycosylated full-length and truncated PrP^C) ranging from 17 to 35 kDa revealed by PrP immunoblotting (insert 1). The post-translational conformational conversion (PTCC) of PrP^C into pathogenic prions (PrP^Sc) changes the 3D structure of PrP^C with the suppression of the three α-helices (H1, H2, and H3) and modification of the two β-sheets (β1 and β2) in favor of a global β-sheet enrichment in PrP^Sc. PrP^Sc displays physicochemical properties distinct from PrP^C, including partial resistance to proteolysis of PrP^Sc submitted to proteinase K (PK) digestion (insert 2). Depending on the nature of PrP^C PTMs, PrP^C PTMs influence, positively or negatively, PrP^C PTCC into PrP^Sc and take part in prion strain selection, prion accumulation, fibril formation, prion neurotoxicity, and spreading of prion infectivity.

Figure 2

Contribution of PrP^Sc-induced PTMs dysregulation of PrP^C membrane partners and coupled signaling effectors to prion neuropathogenesis. In prion diseases, post-translational conformational conversion (PTCC) of PrP^C into PrP^Sc alters PTMs of PrP^C membrane partners in PrP^C signalosomes [Cav1, Fyn, components of focal adhesions (FA)] and deregulates downstream intracellular signaling effectors (NADPH oxidase-NOX, ROCK, PDK1, PDK4). The deregulation of PrP^C-coupled signaling pathways on PrP^C PTCC into PrP^Sc contributes to neurodegeneration through multiple deleterious events: onset of oxidative stress conditions, MAPK/SAPK-dependent neuronal stress, alteration of neuronal polarity and functions, amplification of PrP^Sc and Aβ production, increased vulnerability to TNFα inflammation by reduced shedding of plasma membrane TNFR into sTNFR, and energy metabolism abnormalities. NOX: NADPH oxidase; ROS: reactive oxygen species; ERK: extracellular-regulated kinases; SAPK: stress-associated protein kinases (p38 and JNK); ROCK: RhoA-associated coiled-coil containing kinases; PERK: PKR-related endoplasmic reticulum kinase; PDK1: 3-phosphoinositide-dependent kinase 1; TACE: TNFα converting enzyme; (s)TNFR: (soluble) TNFα receptor; N1: N-terminal fragment of α-cleaved PrP^C; α/β/γ: α-, β-, and γ-secretases; sAPPα: neuroprotective α-cleaved APP fragment; Aβ: neurotoxic amyloid β-peptides; PDK4: Pyruvate Dehydrogenase Kinase 4; PDH: Pyruvate Dehydrogenase. TCA: tricyclic acid cycle or Krebs cycle; β-ox: fatty acid β-oxidation.