Mechanisms of prion-induced neurodegeneration

Abstract

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal neurodegenerative disorders characterised by long incubation period, short clinical duration, and transmissibility to susceptible species. Neuronal loss, spongiform changes, gliosis and the accumulation in the brain of the misfolded version of a membrane-bound cellular prion protein (PrP C ), termed PrP TSE , are diagnostic markers of these diseases. Compelling evidence links protein misfolding and its accumulation with neurodegenerative changes. Accordingly, several mechanisms of prion-mediated neurotoxicity have been proposed. In this paper, we provide an overview of the recent knowledge on the mechanisms of neuropathogenesis, the neurotoxic PrP species and the possible therapeutic approaches to treat these devastating disorders.

Axonal changes in experimental prion diseases recapitulate those following constriction of postganglionic branches of the superior cervical ganglion: a comparison 40 years later

“…Autophagy is highly enhanced in many brain amyloidoses or conformational disorders, Alzheimer's disease, Parkinson's disease [17] and Huntington's disease, in which the signal for autophagy is Huntington [18]. Autophagy is largely regarded as a protective mechanism helping in the removal by organelles of misfolded proteins [19,20].…”

DFT Protocol for EPR Prediction of Paramagnetic Cu(II) Complexes and Application to Protein Binding Sites

“…Prion proteins (PrP c ) are normal cellular proteins involved in various diseases known as transmissible spongiform encephalopathies which include Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep and goats [91,92]. In these pathologies, prion protein undergoes a misfolding in the C-terminal region (128-231) to scrapie form (PrP Sc ) in a process in which the α-helical folded of PrP c becomes a β-sheet forming aggregates [93]. One of the most interesting properties of PrP c is its capability to bind copper [94,95]; in particular, four Cu ions are bound in the "octarepeat" region (60-91) [96,97], and two additional ions in the region 92-111 upon the interaction with His96 and His111 [98,99].…”

PrP (58–93) peptide from unstructured N-terminal domain of human prion protein forms amyloid-like fibrillar structures in the presence of Zn2+ ions

“…[1][2][3][4][5][6] The most spectacular structures of this type are linked to the development of fatal neurodegenerative disorders such as Alzheimer's disease, 7,8 Icelandic type amyloidosis 9,10 or Creutzfeldt-Jakob disease. 11,12 The latter belongs to the group of diseases called transmissible spongiform encephalopathies (TSE) in which a misfolding of human prion protein (PrP) is responsible for the formation of brillar aggregates in the brain. [11][12][13][14][15] Mature form of cellular human prion protein (PrP C ) is 208 residues long glycosylphosphatidylinositol-anchored to outer membrane protein, 16 located in the synaptic cle and expressed at high levels in striatum, hippocampus, cortex and olfactory bulb.…”

“…11,12 The latter belongs to the group of diseases called transmissible spongiform encephalopathies (TSE) in which a misfolding of human prion protein (PrP) is responsible for the formation of brillar aggregates in the brain. [11][12][13][14][15] Mature form of cellular human prion protein (PrP C ) is 208 residues long glycosylphosphatidylinositol-anchored to outer membrane protein, 16 located in the synaptic cle and expressed at high levels in striatum, hippocampus, cortex and olfactory bulb. 17 As shown by NMR studies, human PrP C protein is composed of two structurally different domains: unstructured N-terminal part of polypeptide chain containing residues 23-120 and structured, globular C-terminal domain composed of residues 121-231.…”