The paper by Rachidi et al is a confirmation of our earlier study on human prion diseases. For this paper, the authors provided evidence that PrP populations in an infected cellular environment failed to bind copper. While the mechanisms involved in this aberration is not known, the consequences are clear; including diminished SOD function associated with PrP, impaired cellular antioxidant defenses, diminished Cu content as we and others have shown in human and mouse brains. It is conceivable that this "transformation" by PrP can be attributed to a change in conformation as happen during the conversion from PrPC to PrPSc, or difference in post-translational modifications on the two conformers as suggested by Rachidi et al. However, it must be pointed out that in infected tissues, full-length PrPC and PrPSc are present and the latter can be detected by immunoblotting after affinity purification with an N-terminal anti-PrP and subjected to proteinase K treatment. Therefore, it is incorrect to state that PrPSc are N-terminal truncated and it is also premature to claim that the inability to bind copper is attributed to PrPC in infected cells. Nevertheless, this paper is an essential contribution to a growing body of evidence that changes in Cu homeostasis is a key, but not sole, determinant in the development of prion diseases. Like it or not, a role for metals in prions pathology are here to stay, at least for sometime to come.
References:
Wong BS, Brown DR, Pan T, Whiteman M, Liu T, Bu X, Li R, Gambetti P, Olesik J, Rubenstein R, Sy MS.
Oxidative impairment in scrapie-infected mice is associated with brain metals perturbations and altered antioxidant activities.
J Neurochem. 2001 Nov;79(3):689-98.
PubMed.
Wong BS, Chen SG, Colucci M, Xie Z, Pan T, Liu T, Li R, Gambetti P, Sy MS, Brown DR.
Aberrant metal binding by prion protein in human prion disease.
J Neurochem. 2001 Sep;78(6):1400-8.
PubMed.
Thackray AM, Knight R, Haswell SJ, Bujdoso R, Brown DR.
Metal imbalance and compromised antioxidant function are early changes in prion disease.
Biochem J. 2002 Feb 15;362(Pt 1):253-8.
PubMed.
Comments
Singapore Institute of Technology
The paper by Rachidi et al is a confirmation of our earlier study on human prion diseases. For this paper, the authors provided evidence that PrP populations in an infected cellular environment failed to bind copper. While the mechanisms involved in this aberration is not known, the consequences are clear; including diminished SOD function associated with PrP, impaired cellular antioxidant defenses, diminished Cu content as we and others have shown in human and mouse brains. It is conceivable that this "transformation" by PrP can be attributed to a change in conformation as happen during the conversion from PrPC to PrPSc, or difference in post-translational modifications on the two conformers as suggested by Rachidi et al. However, it must be pointed out that in infected tissues, full-length PrPC and PrPSc are present and the latter can be detected by immunoblotting after affinity purification with an N-terminal anti-PrP and subjected to proteinase K treatment. Therefore, it is incorrect to state that PrPSc are N-terminal truncated and it is also premature to claim that the inability to bind copper is attributed to PrPC in infected cells. Nevertheless, this paper is an essential contribution to a growing body of evidence that changes in Cu homeostasis is a key, but not sole, determinant in the development of prion diseases. Like it or not, a role for metals in prions pathology are here to stay, at least for sometime to come.
References:
Wong BS, Brown DR, Pan T, Whiteman M, Liu T, Bu X, Li R, Gambetti P, Olesik J, Rubenstein R, Sy MS. Oxidative impairment in scrapie-infected mice is associated with brain metals perturbations and altered antioxidant activities. J Neurochem. 2001 Nov;79(3):689-98. PubMed.
Wong BS, Chen SG, Colucci M, Xie Z, Pan T, Liu T, Li R, Gambetti P, Sy MS, Brown DR. Aberrant metal binding by prion protein in human prion disease. J Neurochem. 2001 Sep;78(6):1400-8. PubMed.
Thackray AM, Knight R, Haswell SJ, Bujdoso R, Brown DR. Metal imbalance and compromised antioxidant function are early changes in prion disease. Biochem J. 2002 Feb 15;362(Pt 1):253-8. PubMed.
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