(Have no idea if this is applicable to alpha synuclein and PD, though would very much like to see research into the possibility. Looks as though the therapies aimed at inhibiting amyloid beta in alzheimer's is not such a good idea.)

News:New Scientist
Alzheimer's drugs hurt brain?
Posted by Lauren Urban
[Entry posted at 22nd March 2010 07:10 PM GMT]
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Drugs being investigated for Alzheimer's disease may be causing further neural degeneration and cell death, calling for a change in the way Alzheimer's medications are developed, according to results published in this week's Proceedings of the National Academy of Sciences. ..





Alzheimer's and other neurodegenerative diseases are thought to be caused by amyloids composed of misfolded beta peptides. The accumulation of these can result in the creation of amyloid plaques in the brain, causing cell death. Higher levels of amyloid beta peptides lead to "earlier onset or more severe systems of Alzheimer's disease" said Urbanc, and are believed to be the primary cause of the disease.

Current drug candidates for Alzheimer's disease target these amyloid structures, either by inhibiting the cutting of beta peptides to prevent the formation of amyloids or by creating truncated forms of the beta peptides that do not form amyloids. However, in 2007, one such drug failed Phase III clinical trials because it did not show any cognitive improvement, suggesting that something other than amyloid plaques may be to blame for Alzheimer's disease.

Combining three dimensional computer simulations with hi-res cell imaging and various cellular assays, nano-biophysicist Ratnesh Lal of the University of California San Diego and his colleagues investigated the structure and function of the truncated peptides, known as nonamyloidgenic peptides, formed by some Alzheimer's drug candidates. Surprisingly, the researchers found evidence that these smaller peptides were actually part of the problem. The nonamyloidgenic peptides formed ion channels that caused the cells to take-in very high levels of calcium ions, which damaged synaptic efficiency and eventually killed neurons, causing memory loss.

These "smaller and so-called nonamyloidgenic peptides are indeed toxic by themselves," Lal said. Thus, not only will drug therapies that create nonamyloidgenic peptides not effectively treat the disease, they could increase the speed of degeneration among patients, he said...

"An additional amino acid can change a peptide from somewhat neuroprotective to neurotoxic," Urbanc added. "The hope is that this inspiring work will give rise to novel studies" that examine the roles of secretases and other peptides in neurodegeneration.


Read more: Alzheimer's drugs hurt brain? - The Scientist - Magazine of the Life Sciences http://www.the-scientist.com/blog/di...#ixzz0j2PZBx0A