Proper protein folding will protect neurons
The accumulation of improperly formed protein molecules in nerve cells is characteristic of all neurodegenerative diseases. One of the main mechanisms that ensure the folding (formation of a three-dimensional structure) of proteins are heat shock proteins (chaperones). They are present in the cells of absolutely all organisms and protect them not only from the effects of elevated temperature (this function was simply discovered first), but also from other stressful factors.
Scientists at Duke University Medical Center (Durham, North Carolina), working under the guidance of Dr. Daniel Neef, identified a compound that activates the expression of a protein gene called "Heat Shock Factor-1" (Heat Shock Factor 1, HSF1), which is the main regulator of chaperone synthesis. The authors hope that over time these compounds will transform into effective drugs for the treatment of neurodegenerative diseases, including Huntington's, Alzheimer's and Parkinson's diseases.
To screen small molecules capable of affecting the activity of the HSF1 gene, the authors created a humanized yeast line: they replaced the HSF1 yeast gene with its human counterpart. The resulting yeast died because their cells were unable to make the foreign gene work. The researchers introduced various compounds into the wells with such yeast and observed what was happening. As a result, of the 12,000 small molecules they tested, about 50 ensured the viability of the "humanized" yeast.
After that, the authors decided to analyze the activity of the most promising of these compounds, called HSF1A (HSF1 activator), on the cells of more complex organisms. The results of experiments on mouse embryonic fibroblasts, drosophila cells and the human HeLa cell line showed that HSF1A effectively stimulates the production of chaperone proteins. And the effect of HSF1A on rat nerve progenitor cells with simulated symptoms of Parkinson's disease contributed to the correct formation of protein molecules and their uniform distribution over cell volume, and 4-5 times increased the viability of "sick" neurons.
Further experiments on fruit flies with an analogue of human Parkinson's disease demonstrated that the proposed approach also works for the whole organism. The addition of HSF1A to the drosophila feed caused an increase in the concentration of chaperone proteins in their neurons. This indicates the ability of HSF1A molecules to be absorbed by the gastric mucosa, move through the bloodstream and overcome the blood-brain barrier.
As part of the key experiment of the work, one group of fruit flies with a model of Parkinson's disease received regular food, and the second group received food enriched with HSF1A. As a result, the first group of flies developed eyes that did not have a normal red color with gradually dying photoreceptors, while the eyes of the flies of the second group were completely full-fledged.
The results obtained indicate the great potential of the identified compound as an easy-to-use and effective means for the prevention and treatment of currently incurable neurodegenerative diseases.
The results of the work were published on January 19 in the preliminary on-line version of the journal PLoS Biology in the article "Modulation of Heat Shock Transcription Factor 1 as a Therapeutic Target for Small Molecule Intervention in Neurodegenerative Disease".
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru According to ScienceDaily: Compounds That Help Protect Nerve Cells Discovered.
25.01.2010