Molecular basis of cerebral neurodegeneration in prion diseases

Abstract

The biochemical nature and the replication of infectious prions have been intensively studied in recent years. Much less is known about the cellular events underlying neuronal dysfunction and cell death. As the cellular function of the normal cellular isoform of prion protein is not exactly known, the impact of gain of toxic function or loss of function, or a combination of both, in prion pathology is still controversial. There is increasing evidence that the normal cellular isoform of the prion protein is a key mediator in prion pathology. Transgenic models were instrumental in dissecting propagation of prions, disease‐associated isoforms of prion protein and amyloid production, and induction of neurodegeneration. Four experimental avenues will be discussed here which address scenarios of inappropriate trafficking, folding, or targeting of the prion protein.

Autophagy induction by trehalose counter-acts cellular prion-infection

“…The central feature of these disorders is the conformational change of the hostencoded, cellular prion protein (PrP c ) to an abnormal, partially proteinase K resistant and infectious isoform (PrP Sc ), which finally accumulates in brains of diseased individuals. [1][2][3][4][5] Normally folded and mature PrP c is attached to the outer leaflet of the plasma membrane via a glycosyl-phosphatidyl-inositol (GPI) anchor and conversion of PrP c into PrP Sc seems to take place near the cell surface or along the early endocytic pathway, probably in caveolae-like domains (CLDs) or in rafts (reviewed in ref. 6).…”

Effect of PrP105‑132 on the secretion of interleukin‑6 and interleukin‑8 from microglial cells in�vitro

“…Previous evidence indicates that prion disease is mainly caused by the transformation of normal to abnormal PrP (PrP C to PrP Sc ) (15). PrP C and PrP Sc present the same amino acid sequence but have different spatial configurations.…”

Prions: the danger of biochemical weapons

“…The central feature of these disorders is the conformational change of the host encoded, cellular Prion protein (PrPc), see figures ( Figure 1A and Figure 2B, C) to an abnormal, partially proteinase K resistant and infectious isoform (PrPSc) with an aggregation propensity accumulating in the brain of diseased individuals ( Figure 1B and Figure 2D) Tatzelt & Schätzl, 2007). Cases of vCJD in Great Britain and France raised the possibility that BSE has been transmitted to humans (Bateman et al, 1995;Cousens et al, 1997).…”