Although I know very little of Prana, I'm not sure you're being entirely fair to them. According to the release, they have commenced P11 trials for AD, and are suggesting the platform *might* be equally applicable to CJD. Frankly, given the current numbers of those who suffer from CJD, I'm pleasantly surprised that a BT should be spending money on developing a therapy.
I wouldn't pretend to comment on the science, but the Bush articelwas certainly provocative. I've quoted his introduction below, together with a couple of the articles he cites.
"Until the 1990s, the neuroscience research community paid scant attention to the neurometabolism of metal ions. Apart from a great deal of work done on calcium, and some on magnesium, the neurobiology of the heavier metal ions did not arouse much interest as they were not notably linked to major disease syndromes. This outlook seems set to change dramatically over the coming decade, with a growing number of excellent publications pointing the way to a seminal relationship between Fe, Cu, Mn and Zn in the generation (or defense) of oxygen and protein radicals that mediate the major neurological diseases.
There has been notable resistance in the mainstream of the neuroscience community to the appreciation of the importance of this emerging literature. This is probably because neuroscientists are not usually exposed to the basics of metallochemistry and oxidation chemistry during their training, where the emphasis is on cellular and molecular approaches; and because biochemical training has traditionally de-emphasized the role of metals in metabolic reactions, which is why they have been pejoratively termed 'trace metals'. This is a misnomer because the concentrations of Fe, Zn and Cu in the gray matter are in the same order of magnitude as Mg (0.1–0.5 mM) . Data is rapidly emerging from research on separate diseases, revealing ionic Fe, Cu, Mn and Zn as key neurochemical factors whose interactions with protein targets induce reactions that appear closely relevant to disease pathophysiology. Here, I overview the major contributions to this newly developing field over the last twelve or so months..."
Two papers which the Bush review article
journals.bmn.com.
makes great play of -
Estevez AG, Crow JP, Sampson JB, Reiter C, Zhuang Y, Richardson GJ, Tarpey MM, Barbeito L, Beckman JS:
Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase.
Science 1999, 286: 2498–2500
(according to Bush...)"Most recently, the Beckman laboratory published a superb paper describing a likely mechanism for the pathogenicity of mutant SOD1. The pathogenic SOD1 mutations do not cause a loss of function when the protein is fully loaded with Cu2+ and Zn2+, but do cause a marked loss of affinity for Zn2+ [20]. Estevez et al. observed that altered Cu2+ coordination made Zn-deficient SOD (wild type or mutant) a more efficient oxidant, able to oxidize ascorbate 3000-fold faster than Cu/Zn-SOD. The altered reactivity of Zn-deficient SOD enables it to be reduced by cellular reductants (such as GSH). SOD then donates an electron to O2 to generate O2-, which then reacts with NO to form the strong pro-oxidant, peroxynitrite. Thus, if SOD1 loses Zn2+, its catalytic activity is diminished while it abnormally develops tyrosine nitration activity mediated by O2-, which is formed at the Cu2+ catalytic site [21]. The O2- formed by Zn-deficient SOD1 might not be released as a free intermediate, which would explain why excess SOD1 fails to slow disease progression in FALS/SOD1 transgenic mice [17•]. Intriguingly, Estevez et al. found that apo SOD1 was not neurotoxic in cell culture, whereas Zn-deficient, Cu-loaded SOD1 was neurotoxic, an effect that could be rescued by treatment with Cu2+ chelators, in agreement with reports of the treatment efficacy of Cu2+ chelators upon FALS/SOD1 transgenic mice..."
Brown DR, Wong BS, Hafiz F, Clive C, Haswell SJ, Jones IM:
Normal prion protein has an activity like that of superoxide dismutase.
Biochem J 1999, 344: 1–5. Cited by
(according to Bush...)"The most important paper of the year in this field. PrPc, the cuproprotein that becomes modified, toxic and infectious in TSEs, functions as an SOD. The biochemistry and cell-culture studies in this paper are superb. I know that this paper struggled to be published because reviewers found it hard to accept that such a pathogenic protein could be an SOD-like antioxidant. Thankfully, the editors at Biochemistry Journal saw past this chauvinism...." |
