Prion channel proteins and their role in vacuolation and neurodegenerative diseases

Abstract

The prion encephalopathies, which are characterized by neuropathological changes that include vacuolation, astrocytosis, the development of amyloid plaques and neuronal loss, are associated with the conversion of a normal cellular isoform of prion protein (PrP(c)) to an abnormal pathologic scrapie isoform (PrP(Sc)). The use of PrP[106-126] and its isoforms in studies of channels in lipid bilayers has revealed that it forms heterogeneous channels reflecting modifications in the peptide's structure and differences in the properties of the formed oligomeric aggregates and their intermediates. We propose that the accumulation of pathological isoforms of prion are linked to membrane abnormalities and vacuolation in prion diseases. The interlinked changes in membrane fluidity and endogenous channels induced by prion isoforms can occur independently and concurrently with channel formation, i.e. they are not mutually exclusive. We suggest that vacuolation is a cellular response triggered in order to immobilize pathological prion isoforms having the ability to form channels that compromise cellular membranes. This mechanism is similar to that of other channel-forming proteins that induce vacuolation, e.g. the well-established VacA of Helicobacter pylori, Vero cells and aerolysin, as well as melittin-induced micellization and membrane fusion. We conclude that channel formation is part of the molecular mechanisms responsible for the vacuolation associated with prion diseases. The initial vacuolation could be an adaptive cellular response to compartmentalize the increase in pathogenic prion isoforms, while an excessive accumulation of pathologic prion isoforms in later stages represents the inability of the cell to continue to compartmentalize these misfolded proteins in vacuoles.

Nucleic Acid and Prion Protein Interaction Produces Spherical Amyloids which can Function in vivo as Coats of Spongiform Encephalopathy Agent

“…8,38 The possibility of membrane disruption by PrP SC has been suggested as a cause of cell death. 34,35,65,66 This can cause release of the spheroids in circulation. The spheroid particles are expected to be amenable to isolation from the infected tissues, and their constituents can be characterised.…”

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

“…Equally, it is far from clear how a simple conformational change of a protein leads to the vacuolation or spongiosis (e.g. Aguzzi 2006; Aguzzi et al 2007; Armstrong et al 2001; Chung et al 1999; Crozet et al 2008; Diedrich et al 1991; Foster et al 2001; Julius et al 2008; Kourie 2002; Mallucci et al 2003; Mallucci et al 2007; Miele et al 2001; Sakudo and Ikuta 2009a, b; Westaway et al 1994; Williams et al 1997) (formation of holes) in brain tissue characteristic of late-stage prion disease (and indeed of Alzheimer’s (Erkinjuntti et al 1996; Sakudo and Ikuta 2009a). The question then arises as to whether it is possible that PrP Sc modifies iron metabolism in an unfavourable way (and/or vice versa), not least since prion proteins bear phylogenetic relationships to the ZIP family of metal ion transporters (Schmitt-Ulms et al 2009).…”

Mixtures of Wild-type and a Pathogenic (E22G) Form of Aβ40 in Vitro Accumulate Protofibrils, Including Amyloid Pores

“…49 Furthermore, several amyloidforming proteins that are associated with neurodegenerative diseases (Alzheimer's disease, Huntington disease and prion disease) have been demonstrated to form ion-permeable pores in vitro, at concentrations that are toxic in cell cultures. In addition, the tendency of amyloid proteins (including Ab, 27,50 islet amyloid peptide amylin, 51,52 polyglutamine repeats, 53 serum amyloid A, 54 b2-microglobulin, 55 prion proteins 56,57 and a-synuclein 30,58,59 ) to form ion-permeable pores correlates with the presence of the pore-like structures. Thus, membrane disruption via pore formation may be a general mechanism of cytotoxicity for neurodegenerative diseases.…”