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New Method Uses Yeast and Stem Cells to Reveal Promising Drug Targets

Posted on November 28, 2013

In laboratory studies using yeast and human cells, scientists have discovered a compound that reverses the toxic effects of alpha-synuclein, the protein that accumulates in certain brain cells, leading to Parkinson’s disease (PD). The studies, supported in part by the Parkinson’s Disease Foundation (PDF), were published online in two reports in the October 24 issue of Science Express.

Typically, one of the first steps in testing whether a chemical compound might be an effective new drug is to see how it interacts with target molecules in test tubes. Researchers led by Susan Lindquist, Ph.D., at the Whitehead Institute in Cambridge, Massachusetts, have developed an alternative — a way to test potential therapies in living yeast cells, which are surprisingly similar to human cells. After creating a strain of yeast with the hallmark of the disease — alpha-synuclein protein build-up inside the cells — they screened nearly 200,000 drug compounds. They found one that could reverse the toxic effects of alpha-synuclein.

A second study was then led by Vikram Khurana, M.D., Ph.D., a contributor to the yeast study, who was supported by the PDF-ABF Clinician-Scientist Development Award (jointly funded and sponsored by PDF and the American Brain Foundation). He and his colleagues tested the compound in human nerve cells that carried mutations in the alpha-synuclein gene. These nerve cells were created by transforming the skin cells of two people with genetic PD into stem cells: a woman carrying a mutation in the alpha-synuclein gene and a man who had three copies of the alpha-synuclein gene.

Results

  • The researchers first identified the toxic effects of alpha-synuclein in yeast cells, including cellular stress and a build-up of waste products.
  • The researchers then proved that these effects were found in the human neurons and were due to the alpha-synuclein mutation.
  • A chemical compound identified in studies with yeast, called NAB2 (an N-aryl benzimidazole analog) successfully reversed the toxic effects in the human neurons.

What Does It Mean?

This study demonstrates a new way of discovering potential new drugs for PD and other neurodegenerative diseases.

Indeed, Dr. Khurana and his colleagues proved the effectiveness of the new drug-screening method by identifying a chemical compound that may have the potential to treat Parkinson’s. The compound works by reversing the toxicity of alpha-synuclein. While it is widely known that alpha-synuclein accumulates in aggregates in the brains of people with PD, it is still unclear whether alpha-synuclein is acting alone, triggered by something else similar to an avalanche, or whether it accumulates because something else is also toxic to the cell. If alpha-synuclein is found to be the toxic cause of PD, this compound sounds promising for drug development.

To move forward, scientists must test the compound in animal models of Parkinson’s. If successful and safe for animals, the compound must then undergo similar testing in humans.

Many years in the making, this success of this new method underscores the vital need to support basic research in the effort to end Parkinson’s — a need that is wholeheartedly endorsed by PDF.

Source: Parkinson’s Disease Foundation

   
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