25 Aug 2004

August 25 2004. Protein misfolding and aggregation link Alzheimer's disease with familiar neurodegenerative disorders such as prion disorders or Parkinson's disease, but also some further afield, such as retinitis pigmentosa. In this disorder, neurons in the retina degenerate, perhaps as a consequence of misfolding and aggregation of the photoreceptor rhodopsin, leading first to loss of night vision and, later, peripheral vision.

In an article published in the August 20 edition of the Journal of Biological Chemistry, researchers describe a facet of rhodopsin folding that should catch the attention of AD researchers, namely, that zinc plays a critical role in the structural integrity of rhodopsin.

Zinc has emerged as a molecule of interest following findings that addition of the metal promotes in-vitro aggregation of rhodopsin, much as it seems to promote aggregation of prion proteins and Aβ (see ARF related news story). Interestingly, though somewhat paradoxically, there is a zinc deficiency syndrome that recapitulates the retinal degeneration and night blindness of retinitis pigmentosa.

Some 100 heritable mutations in the G protein-coupled rhodopsin have been found to cause retinitis pigmentosa, and in their previous research, John Hwa's team at Dartmouth University in Hanover, New Hampshire, had found a cluster of these in a transmembrane region of the protein. In their current paper, first author Aleksandar Stojanovic and colleagues find that this corresponds to the location of a high-affinity, physiologically relevant Zn2+ coordination site.

This site turns out to be a stabilizing site for rhodopsin. By making point mutations within and near the high-affinity Zn2+ site, the authors determined that the nearby residues His211 and Glu122 are critical in coordinating the Zn2+ binding and preserving rhodopsin's proper folding and thermal stability.

The authors propose that disruptions of this site by disease-causing point mutations lead to rhodopsin misfolding and resultant night blindness, and suggest that a therapeutic approach to retinitis pigmentosa might then be to improve zinc binding to the transmembrane region of the light receptor.

But what about the seemingly contrary evidence that excess Zn2+ promotes aggregation of rhodopsin, Aβ, or prions. Interestingly, one of three, lower-affinity, solvent exposed Zn2+ coordination sites identified by the authors turned out to be a protein-destabilizing site, particularly in situations of elevated nonphysiological levels of Zn2+. The authors also note evidence that low-affinity metal coordination sites may not be quite so particular about which metals they bind. Thus, excess copper might also use such a mechanism to promote the formation of amyloid in Alzheimer's. Given this possibility, it will be interesting to follow the progress of efforts to rid the AD brain of excess metals by chelation (see ARF related news story).—Hakon Heimer

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

1. Synaptic Zinc Fingered As Critical In Plaque Formation 22 Nov 2002
2. Pilot Study Suggests Clioquinol Benefits AD Patients 3 Jan 2004

Further Reading

No Available Further Reading