Corporate Banner
Satellite Banner
Stem Cells, Cellular Therapy & Biobanking
Scientific Community
Become a Member | Sign in
Home>News>This Article

Yeast, Human Stem Cells Drive Discovery of New Parkinson’s Disease Drug Targets

Published: Wednesday, October 30, 2013
Last Updated: Wednesday, October 30, 2013
Bookmark and Share
Using a discovery platform whose components range from yeast cells to human stem cells, scientists have identified a novel Parkinson’s disease drug target.

The platform—whose effectiveness is described in dual papers published online this week in the journal Science—could accelerate the discovery of drug candidates that address the underlying pathology of Parkinson’s and other neurodegenerative diseases. Today, no such drugs exist.

Parkinson’s disease (PD) and such neurodegenerative diseases as Huntington’s and Alzheimer’s are characterized by protein misfolding, resulting in toxic accumulations of proteins in the cells of the central nervous system. Cellular buildup of the protein alpha-synuclein, for example, has long been associated with PD, making this protein a seemingly appropriate target for therapeutic intervention.

In the search for compounds that might alter a protein’s behavior or function—such as that of alpha-synuclein—drug companies often rely on so-called target-based screens that test the effect large numbers of compounds have on the protein in question in rapid, automated fashion. Though efficient, such an approach is limited by the fact that it essentially occurs in a test tube. Seemingly promising compounds emerging from a target-based screen may act quite differently when they’re moved from the in vitro environment into a living setting.

To overcome this limitation, the lab of Whitehead Member Susan Lindquist has turned to phenotypic screens in which candidate compounds are studied within a living system. In Lindquist’s lab, yeast cells—which share the core cell biology of human cells —serve as living test tubes in which to study the problem of protein misfolding and to identify possible solutions. Yeast cells genetically modified to overproduce alpha-synuclein serve as robust models for the toxicity of this protein that underlies PD.

“Phenotypic screens are probably underutilized for identifying drug targets and potential compounds,” says Daniel Tardiff, a scientist in the Lindquist lab and lead author of one of the Science papers. “Here, we let the yeast tell us what is a good target. We let a living cell tell us what’s critical for reversing alpha-synuclein toxicity.”

In a screen of nearly 200,000 compounds, Tardiff and collaborators identified one chemical entity that not only reversed alpha-synuclein toxicity in yeast cells, but also partially rescued neurons in the model nematode C. elegans and in rat neurons. Significantly, cellular pathologies including impaired cellular trafficking and an increase in oxidative stress, were reduced by treatment with the identified compound. Enabled by the chemistry provided by Nate Jui in the Buchwald lab at MIT, Tardiff found that the compound was working by restoring functions mediated by a cellular protein critical for trafficking that was previously thought to be “undruggable.”

But would these findings apply in human cells? To answer that question, husband-and-wife team Chee-Yeun Chung and Vikram Khurana led the second study published in Science to examine neurons derived from induced pluripotent stem (iPS) cells generated from Parkinson’s patients. The cells and differentiated neurons (of a type damaged by the disease) were derived from patients that carried alpha-synuclein mutations and develop aggressive forms of the disease. To ensure that any pathology developed in the cultured neurons could be attributed solely to the genetic defect, the researchers also derived control neurons from iPS cells in which the mutation had been corrected.

Chung and Khurana used the wealth of data from the yeast alpha-synuclein toxicity model to clue them in on key cellular processes that became perturbed as patient neurons aged in the dish. Strikingly, exposure to the compound identified via yeast screens in Tardiff’s study reversed the damage in these neurons.

“It was remarkable that the compound rescued yeast cells and patient neurons in similar ways and through the same target—a target we would not have identified without yeast genetics to guide us,” says Khurana, a postdoctoral scientist in the Lindquist lab and a neurologist at Massachusetts General Hospital who recruited patients for participation in this research. Khurana believes that the abnormalities discovered occur in the early stages of disease. If so, successful manipulation of the targets identified here might help slow or even prevent disease progression.

For the researchers involved, these findings are a bit of surprise. Because neurodegenerative disorders like PD are largely diseases of aging, modeling them in a culture dish using neurons grown from iPS cells has been thought to be exceedingly difficult, if not impossible.

“Many, ourselves included, were skeptical that we could find any important pathologies for a neurodegenerative disorder by reprogramming patient cells,” says Chung, a Senior Research Scientist in the Lindquist lab. “Critically, we also validated these pathologies in post-mortem brains, so we’re quite confident these are relevant for the disease.”

Next steps for these scientists include chemically optimizing the compound identified and testing it in animal models. Moreover, they are convinced that this yeast-human stem cell discovery platform could be applied to other neurodegenerative diseases for which yeast models have been developed.

“Using yeast genetics to identify a compound and its mechanism of action against the fundamental pathology of a disease illustrates the power of the system we’ve built,” says Lindquist, who is also professor of biology at MIT and a Howard Hughes Medical Institute investigator. “It’s critical that we continue to leverage this power because as we reduce the rate at which people are dying from cancer and heart disease, the burden of these dreaded neurodegenerative diseases is going to rise. It’s inevitable.”

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,600+ scientific posters on ePosters
  • More than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Scientists Identify Gene that Controls Aggressiveness in Breast Cancer Cells
Researchers have identified a transcription factor, known as ZEB1, that is capable of converting non-aggressive basal-type cancer cells into highly malignant, tumor-forming cancer stem cells (CSCs).
Monday, July 08, 2013
Precision Gene Targeting in Stem Cells Corrects Disease-Causing Mutations
Whitehead Institute researchers manipulate targeted genes in both human embryonic stem cells and induced pluripotent stem cells.
Tuesday, July 19, 2011
Whitehead Member Rudolf Jaenisch Honored for Groundbreaking Stem Cell Research
Israel’s Wolf Foundation has named Whitehead Institute Founding Member Rudolf Jaenisch a recipient of the prestigious 2011 Wolf Prize in Medicine.
Friday, February 18, 2011
Embryonic Stem Cells Reveal Oncogene's Secret Growth Formula
Researchers describes a pausing step in the transcription process that serves to regulate expression of as many as 80% of the genes in mammalian cells.
Monday, May 03, 2010
Technique Enables Efficient Gene Targeting In Human Embryonic Stem Cells
Whitehead scientists have developed a technique to modify or introduce genes into the genomes of human ESCs and iPS cells.
Thursday, August 27, 2009
Novel Cell Lines Propel the Search for Safer Stem Cell Induction
Researchers produce mice and mouse cell lines with identical configurations of the specific factors needed to reprogram adult cells to an embryonic-stem-cell-like state.
Thursday, January 22, 2009
Single Virus Used to Convert Adult Cells to Embryonic Stem Cell-Like Cells
Researchers have simplified the creation of induced pluripotent stem cells, cutting the number of viruses used in the reprogramming process from four to one.
Monday, December 22, 2008
Recipe for Cell Reprogramming Adds Protein
A drug-like molecule can be substituted for the cancer gene c-Myc, one of four genes added to adult cells to reprogram them to an embryonic-stem-cell-like state, says Whitehead researchers.
Friday, August 08, 2008
Putting microRNAs on the Stem Cell Map
Whitehead researchers have now discovered how microRNAs fit into the map of embryonic stem cell circuitry.
Friday, August 08, 2008
Scientists Identify Gene that Regulates Polarity in Regenerating Flatworms
Whitehead scientists have discovered that the gene Smed-beta-catenin-1 is required for proper decisions about head-versus-tail polarity in regenerating flatworms.
Monday, December 10, 2007
Reprogrammed Adult Cells Treat Sickle-Cell Anemia in Mice
Mice with a human sickle-cell anemia disease trait have been treated successfully by directly reprogramming their own cells to an embryonic-stem-cell-like state, without the use of eggs.
Monday, December 10, 2007
Adult Stem Cells Lack Key Pluripotency Regulator
A study by Whitehead researcher has shown that protein Oct4 is not required to maintain mouse adult stem cells in their undifferentiated state.
Wednesday, October 17, 2007
How Embryonic Stem Cells Maintain Their Identity
Two studies report details of the "genetic program" that affords embryonic stem cells the flexibility to give rise to any cell type in the body.
Wednesday, April 26, 2006
Scientific News
Snapshot Turns T Cell Immunology on its Head
New research may have implications for 1 diabetes sufferers.
Developing a Gel that Mimics Human Breast for Cancer Research
Scientists at the Universities of Manchester and Nottingham have been funded to develop a gel that will match many of the biological structures of human breast tissue, to advance cancer research and reduce animal testing.
Lung Repair and Regeneration Gene Discovered
New role for hedgehog gene offers better understanding of lung disease.
Restoring Vision with Stem Cells
Age-related macular degeneration (AMRD) could be treated by transplanting photoreceptors produced by the directed differentiation of stem cells, thanks to findings published today by Professor Gilbert Bernier of the University of Montreal and its affiliated Maisonneuve-Rosemont Hospital.
The Age of Humans Controlling Microbes
Engineered bacteria could soon be used to detect environmental toxins, treat diseases, and sustainably produce chemicals and fuels.
Gene Expression: A Snapshot of Stem Cell Development
New genes found that regulate development of stem cells.
Tissue-Engineered Colon from Human Cells
A study by scientists at Children’s Hospital Los Angeles has shown that tissue-engineered colon derived from human cells is able to develop the many specialized nerves required for function, mimicking the neuronal population found in native colon.
Tension Helps Heart Cells Develop Normally in the Lab
Stanford engineers have uncovered the important role tension plays in growing heart cells out of the body.
Urine Excretion From Stem Cell-Derived Kidneys
Researchers report a strategy for enabling urine excretion from kidneys grown from stem cells.
Stem Cell Research Hints at Evolution of Human Brain
Researchers at UC San Francisco have succeeded in mapping the genetic signature of a unique group of stem cells in the human brain that seem to generate most of the neurons in our massive cerebral cortex.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,600+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos