Small molecules that appear to be capable of protecting brain cells from alpha-synuclein toxicity, a hallmark of Parkinson's disease, has been claimed by Whitehead Institute researchers, to have been identified.
During the study, the team came across four related small molecules that prevented the development of several cellular traits associated with Parkinson's disease, including the accumulation of alpha-synuclein deposits in the cell, improper protein trafficking from one organelle to another, and damage inflicted on the cells' engines, the mitochondria.
"In this research, we used yeast as a Parkinson's disease model system to identify the compounds that really work in two higher order model systems of Parkinson's," said Julie Su, a first co-author on the paper describing the research and a former postdoctoral researcher in Whitehead Member Susan Lindquist's lab.
The yeast was modified to produce too much of the alpha-synuclein protein in its cells. The resulting cells manifest adverse effects similar to those experienced in brain cells from Parkinson's patients.
Using this yeast strain, the Lindquist team screened 115,000 small compounds to see which ones alleviate the Parkinson's-like traits. During a screen, a compound is added to a small amount of yeast
Four compounds were found to restore the alpha-synuclein yeast cells' growth to 50pc of normal yeast cells. Yeast cells that were not treated with the compounds died.
The researchers also identified two commercially available compounds with similar chemical structures and used those in further tests.
In the study conducted using round worm Caenorhabditis elegans and rat neurons, the first four compounds were able to rescue the round worms, while in the rat neurons, three of the four original compounds and one of the commercial compounds improved the nerve cells' growth.
"Those two things are obviously related," said Pavan Auluck, first co-author and a visiting scientist in the Lindquist lab.
"We're trying to figure out what the connections are between them. And there are a number of ways they can be related," Auluck added.
"There are very deeply rooted processes that connect protein trafficking and mitochondrial viability," said Lindquist, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. "That emphasizes that the underlying problem caused by alpha-synuclein is a general cellular defect that is part of the machinery of all eukaryotic cells. The specific problems in Parkinson's are due to the neurons being particularly sensitive to that process going awry."
The study appears in Disease Models and Mechanisms (DMM).