The Relevance Prion Protein Function And Copper Binding To Prion Disease

If loss of prion protein function has consequences for disease progression in prion diseases, then one would expect that the earliest changes in prion disease would be seen at the synapse. Recent studies of changes in neurones in experimental prion disease have identified loss of dendritic spines occurring before any other change in prion disease (78). However, such changes, although fitting with the hypothesis that loss of prion protein function contributes to neurodegeneration in prion disease, do not prove the connection.

As already mentioned, PrPC expression is necessary if not sufficient for prion disease (7). However, animals lacking PrPC expression do not develop a spontaneous form of prion disease. Nevertheless, these mice do have a phenotype indicative of a disturbance and neurones lacking PrPC expression in particular are more sensitive to oxidative stress. PrPC-deficient cells have diminished cellular activity of SOD and diminished copper content.

Studying neurodegeneration in vivo has been a problem in prion disease. Insights into the mechanism by which PrPSc is neurotoxic have come from cell culture studies using the peptide mimic of PrPSc, PrP106-126 (32,33,60,64). This peptide has effects on cells that include reducing their resistance to oxidative stress and decreasing activity of SOD in cells (32). Studies with similar peptides have suggested that PrP106-126 could bind directly to PrPC in the vicinity of the palendromic repeat, which, as suggested earlier may be the active site of the protein (79). This interaction directly inhibits the SOD activity of PrPC (56,74). Furthermore, PrPSc can also inhibit the activity of PrPC. In a reactive environment such as the damaged brain, this would expose neurones to the toxicity of substance such as superoxide generated by microglia or excess neurotransmitters such as glutamate, which can activate intracellular production of superoxide.

PrP106-126 also inhibits copper uptake. This effect is seen only in cells expressing PrPC (74). This inhibition of copper uptake is thus probably a result of interaction between PrP106-126 and PrPC at the cell surface. This interaction would have a similar effect to a PrP knockout phenotype, implying a loss of function of PrPC. The consequences of this are decreased incorporation of copper into enzymes such as SOD (80). This would further compromise cellular resistance to oxidantive stress. Although not conclusive, these observations are pointing in the direction that loss of PrPC function is a disadvantage for a cell. In a healthy animal, this disadvantage might not lead to death,

Fig. 6. Metals in the brains of patients with CJD were measured using mass spectroscopy. Changes in manganese and copper were observed suggesting that prion disease causes dramatic changes in the metal content of the brain. These changes may be a result of the disease but they suggest that prion diseases involve disturbances to the metabolism of trace elements. Shown are the mean and SEM of nine results for CJD patients (gray bars) and three for control patients (open bars).

Fig. 6. Metals in the brains of patients with CJD were measured using mass spectroscopy. Changes in manganese and copper were observed suggesting that prion disease causes dramatic changes in the metal content of the brain. These changes may be a result of the disease but they suggest that prion diseases involve disturbances to the metabolism of trace elements. Shown are the mean and SEM of nine results for CJD patients (gray bars) and three for control patients (open bars).

Fig. 7. The critical question as regards prion disease is how conversion of the normal cellular isoform (PrPC) to the disease-specific isoform (PrPSc) causes neurones to die. It is likely that the conversion of PrPC to PrPSc results in a loss of PrPC function without upregulation of compensatory mechanisms. These upregulatory mechanisms would probably be active when there is no PrPC expression detected by the cells. Although this loss of function might not induce cell death on its own, the neurone, having lost functional PrPC, might be more susceptible to the toxicity of substances generated in the brain as a reaction to the presence of inflammatory PrPSc. This combination of effects might then lead to neuronal death.

Fig. 7. The critical question as regards prion disease is how conversion of the normal cellular isoform (PrPC) to the disease-specific isoform (PrPSc) causes neurones to die. It is likely that the conversion of PrPC to PrPSc results in a loss of PrPC function without upregulation of compensatory mechanisms. These upregulatory mechanisms would probably be active when there is no PrPC expression detected by the cells. Although this loss of function might not induce cell death on its own, the neurone, having lost functional PrPC, might be more susceptible to the toxicity of substances generated in the brain as a reaction to the presence of inflammatory PrPSc. This combination of effects might then lead to neuronal death.

but in an animal in which an inflammatory response has been initiated, loss of active PrPC would be a clear disadvantage.

Recently studies of transition metals in prion diseases have begun to emerge. Studies of the brain of CJD patients have shown that the levels of copper in their brains are decreased (81) (Fig. 6). Similar studies with mice experimentally infected with the disease scrapie confirm this result. The changes in copper in this model precede neruonal death and follow the course of PrPSc generation in the brain. Furthermore, analysis of PrPSc isolated from the brain of CJD patients and mice with scrapie has shown that this protein lacks significant copper binding and the antioxidant activity associated with PrPC has been lost completely. This implies that prion disease does cause a loss of PrPC function that is directly related to the ability of the protein to bind copper. Maintaining functional PrPC is clearly advantageous and there is evidence to suggest this can protect against prion disease (Fig. 7). PrP knockout mice that have been modified to express hamster PrP via a GFAP promoter express PrPC only in astrocytes. These mice are susceptible to infection with hamster scrapie and develop prion disease (82). Wild-type mice are highly resistant to hamster scrapie because of specific differences between the protein sequence of hamster and mouse PrPC. However, if wild-type mice are made transgenic to express hamster PrPC in astrocytes, they cannot be infected with hamster scrapie. The implication of this is that mouse PrPC, which cannot be converted to mouse PrPSc by hamster PrPSc, protects against prion disease. This suggests that where there is sufficient functional PrPC, neurones may be protected from neuronal death caused by prion disease. In years to come, strategies that protect or restore the normal copper-dependent functions of PrPC might be useful therapeutics to treat or prevent prion disease.

In the future years, we may see a deeper understanding of the nature and cause of prion disease, but, in parallel, we are likely to see the prion protein become accepted as a cuproprotein essential to normal neuronal survival and function.

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