Toward a Mechanism of Prion Misfolding and Structural Models of PrP^Sc: Current Knowledge and Future Directions

Abstract

Despite extensive investigation, many features of prion protein misfolding remain enigmatic. Physicochemical variables known to influence misfolding are reviewed to help elucidate the mechanism of prionogenesis and identify salient features of PrP Sc , the misfolded conformer of the prion protein.Prospective work on refinement of candidate PrP Sc models based on thermodynamic considerations will help to complete atomic-scale structural details missing from experimental studies and may explain the basis for the templating activity of PrP Sc in disease.

Extracellular vesicles round off communication in the nervous system

“…These aggregates are usually fibrillar structures (referred to as amyloid) and contain the misfolded protein in a β-sheet conformation; amyloid may subsequently cause tissue damage and cell death. Prion-like properties, such as those observed for prion protein (PrP) in Creutzfeldt–Jakob disease 65 , have been suggested for other proteins involved neurodegenerative disorders. Such proteins include amyloid-β and tau in AD 66,67 ; α-synuclein in Parkinson disease 68 ; and TAR DNA-binding protein 43 (TDP43), copper zinc superoxide dismutase 1 (SOD1) and other proteins in amyotrophic lateral sclerosis and frontotemporal lobal degeneration 69 .…”

Role of Exosomes/Microvesicles in the Nervous System and Use in Emerging Therapies

“…Extracellular membrane vesicles have been implicated in the spread of toxic proteins within the nervous system in a number of neurodegenerative diseases, including transmissible spongiform encephalopathies, Alzheimer’s disease (AD), Parkinson’s disease (PD), tauopathies, and amyotrophic lateral sclerosis (ALS; for review see Vingtdeux et al, 2007; Vella et al, 2008; Guest et al, 2011; Frühbeis et al, 2012). In all these diseases mutated or “misfolded” proteins serve as templates for formation of protein oligomers that accumulate and interfere with neuronal function, eventually leading to cell death.…”

“…This concept of the tendency of some proteins to seed their own aggregation with “infectious” delivery via EMVs has been implicated in a number of neurodegenerative diseases. Interestingly, in many of these diseases there is a spatiotemporal propagation of the pathology suggesting cell-to-cell spread (Guest et al, 2011), which for non-secreted proteins could be mediated by EMV transfer or nanotubes (Rustom et al, 2004; Gousset and Zurzolo, 2009). …”

Role of Protein Aggregation in Neurodegenerative Diseases

“…In particular, free radicals and ROS (reactive oxygen species) cause protein oxidation. A variety of oxidants can be occurred in normal aerobic metabolism [20]. Also, lack of antioxidants, excess of oxygen and lipid and metal ions can generate free radicals.…”