Chaperones and redox enzymes, such as peroxidases, play major roles in keeping eukaryotic cells free from the ravages of reactive oxygen species (ROS), which are thought to play a pathological role in many neurodegenerative diseases, including Alzheimer’s. Redox enzymes metabolize ROS before they can do their dirty work, and if that fails, chaperones prevent ROS-induced protein misfolding and aggregation. Both these defense mechanisms have seemed mutually exclusive—until now. In the May 28 Cell, Sang Yeol Lee and colleagues from Gyeongsang National University, Chinju, Korea, show that two peroxiredoxin enzymes found in yeast can also function as chaperones.
Peroxiredoxins are a class of peroxidases only recently discovered. They exist in most eukaryotic cells, including humans. While peroxiredoxins use thioredoxin to reduce hydrogen peroxide, some of them have been shown to form oligomers that structurally resemble small heat shock proteins. This prompted Lee and colleagues to test yeast peroxiredoxins for chaperone-like activity.
First author Ho Hee Jang and colleagues challenged yeast that carry only a mutant form of the peroxiredoxin Prx1 that has no peroxidase activity. Significantly, this mutant enzyme can still rescue yeast from heat shock. When Jang and colleagues examined the effect of heat shock on Prx1, they found that the protein formed high molecular-weight species with ring-like structures similar to those of other chaperones. In addition, Jang found that adding hydrogen peroxide induced the same reconfiguration of the peroxiredoxin. But when the authors examined chaperone and peroxidase activity of monomeric and multimeric forms of the protein, they found that the largest molecules had no peroxidase activity, and the smallest had no chaperone activity. The results indicate that heat shock, or oxidative stress, act as switches to convert the peroxidase into a chaperone.
Though this work was carried out on yeast peroxiredoxins, it clearly has implications for mammalian cells, which harbor Prx1 homologs. In this respect, it is worth noting that Jang and colleagues report preliminary evidence that Prx1 prevents the denaturation and aggregation of α-synuclein mediated by oxygen radicals. This suggests that peroxiredoxins may play a role in preventing Parkinson’s and possibly other neurodegenerative diseases. It has been shown, for example, that human PrxI and PrxII are significantly elevated in both Alzheimer’s disease and Down’s syndrome (see Kim et al., 2001).—Tom Fagan
- Kim SH, Fountoulakis M, Cairns N, Lubec G. Protein levels of human peroxiredoxin subtypes in brains of patients with Alzheimer's disease and Down syndrome. J Neural Transm Suppl. 2001;(61):223-35. PubMed.
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- Jang HH, Lee KO, Chi YH, Jung BG, Park SK, Park JH, Lee JR, Lee SS, Moon JC, Yun JW, Choi YO, Kim WY, Kang JS, Cheong GW, Yun DJ, Rhee SG, Cho MJ, Lee SY. Two enzymes in one; two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function. Cell. 2004 May 28;117(5):625-35. PubMed.