Just a few weeks ago, the Nobel Prize in Physiology or Medicine was awarded to three scientists: Dr. Randy Schekman, Dr. Thomas Südhof, and Dr. James Rothman. These three men were rewarded for their work on a curious organism we encounter in our everyday lives. This Nobel Prize-worthy creature is yeast. It might be surprising that studies on an organism we use to ferment beer and make bread rise can also be applicable to human biology and therapeutics. However, yeast is a ubiquitous tool that has been used by biologists and geneticists around the world to study basic human biological processes for decades. Yeast is an excellent model for human disease because we share many cellular structures and functions with this fascinating organism. In addition, yeast is classified in the same evolutionary group (domain) as humans: Eukarya! Other advantages to using yeast instead of other organisms for scientific studies are that yeast are simple, unicellular, easy to grow and maintain, and can be controlled genetically with exquisite precision [1]. In fact, the first eukaryote to have its genome sequenced was the yeast strain Saccharomyces cerevisiae, the same strain we use in baking and brewing. Since then, scientists have genetically engineered many new strains of yeast to express various human proteins. These models allow scientists to study the function and importance of such proteins so we develop a better understanding of complicated human diseases. In the end, such studies are a crucial stepping-stone in our search for new drugs to treat crippling neurodegenerative diseases like Parkinson’s disease (PD).

Parkinson’s disease and alpha-synuclein

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s [2]. Since age is the main risk factor for PD and life expectancy is increasing, the prevalence of PD is expected to rise as well. Classic symptoms of PD include impaired voluntary movement (difficulty in starting and controlling a movement), increased involuntary movement (inability to remain still or in a relaxed position), and decreased cognition (slow responses to questions and detachment from conversations) [2]. These symptoms are caused by the death of neurons (See Figure 1 [3]) in the brain, which can be caused by oxidative stress, mitochondrial dysfunction, and the formation of toxic protein tangles called “Lewy Bodies.” These tangles are a visible hallmark of PD that build up inside neurons. Researchers have been able to attribute this phenomenon to the over-production of a small protein called alpha-synuclein [4]. The normal cellular role of this protein is poorly understood, but it is known to associate with neuron vesicles that contain and transport dopamine, and seems to have a role in helping neurons maintain their shape [5]. Alpha-synuclein is likely involved in causing the symptoms of PD, which makes it an appealing drug target for scientists.

Figure 1. Schematic representation of the neuron pathways in the brain that are affected by PD. The left side shows pathways in non-diseased brains. The right side shows pathways in PD brains. Blue arrows indicate increased activity of the area. Red arrows indicate decreased activity of the area. In PD, some pathways are strengthened, weakened, or obliterated. From [3].

Drug screening in yeast

Traditional drug discovery relies on “target-based” screens that test the effect of thousands of drugs (alone or in combinations) on isolated protein that is put on a plastic plate [6]. Although this method is quick and easy, it may not always identify physiologically relevant drugs because the protein has been removed from its cellular context [7]. To screen for novel PD drugs, Professor Susan Lindquist at the Massachusetts Institute of Technology has utilized yeast as a model for toxic alpha-synuclein protein behavior. To set up the system, she genetically modified yeast to mimic PD neurons by over-producing alpha-synuclein. This new strain was then used to screen over 180,000 drug-like compounds. One chemical from the screen looked promising: N-Aryl Benzimadazole (NAB) [8].

To confirm that the drug was applicable to neurons, Dr. Lindquist turned to another commonly used model organism, the worm Caenorhabditis elegans. These worms experience neuron degeneration in an age-dependent manner just as humans do. In worms, the drug was effective in mitigating the effects of PD: alpha-synuclein toxicity was reversed, and the drug partially rescued neurons from other PD-related dysfunction.

The next step was to prove this drug would work in mammals. To accomplish this, rat brain cells that overexpress alpha-synuclein were exposed to increasing concentrations of the drug. Both the expression of alpha-synuclein and the severity of other PD-related effects decreased as more drug was used to treat the cells.

The results from these tests were remarkable, but could they apply to human cells? To answer this question, neurons were taken from human PD patients and cultured in the laboratory. When these neurons were treated with the drug, Dr. Lindquist observed that, just like in the rat cells, expression of alpha-synuclein and other PD-related cellular stress factors decreased [7].

The results of this yeast screen are truly remarkable. Neurodegenerative disorders are diseases of aging, so modeling the disease in an organism that has a short life span like yeast may at first have seemed impossible. Not only that, but because yeast cells are functionally different from neurons, it’s not obvious that drugs discovered in a yeast screen would actually work in organisms all the way up to mammals. Indeed, many aspects of neuron behavior are beyond the capacity of yeast to replicate [9]. Things like synaptic transmission, the process where chemicals from one neuron are released to influence another neuron, can never be recapitulated in yeast. However, yeast can faithfully reproduce phenomenon seen in diseased neurons that cause neurodegeneration.

The study discussed here is an excellent example of how powerful of a tool yeast can be in modern drug discovery for the treatment of neurodegenerative diseases. The drug, NAB, has the potential to go into clinical trials to treat PD patients and if successful, may even one day be on the shelves your nearest local pharmacy. Given the importance of this organism for understanding and exploring human health and development, it is no wonder that Schekman, Südhof, and Rothman were awarded the Nobel Prize this year for dedicating their lives to understanding the inner workings of our microscopic friends, yeast.

Elaine Garcia is a graduate student in the Biological and Biomedical Sciences Ph.D. program at Harvard Medical School.

References:

[1] Simon, Julian A., Bedalov, Antonio, (2004) Yeast as a model system for anticancer drug discovery. Nature Reviews Cancer, 4, 481-487.

[2] Mayo clinic staff. (2012) Parkinson’s disease. http://www.mayoclinic.com/health/parkinsons-disease/DS00295

[3] Medicus of Borg. DA-loops in PD (2006) http://commons.wikimedia.org/wiki/File:DA-loops_in_PD.jpg

[4] Obeso, Jose A., et al. (2010) Missing pieces in the Parkinson’s disease puzzle. Nature Medicine, 16, 653-661.

[5] Bendor, Jacob T., Logan, Todd P., Edwards, Robert H., (2013) The function of alpha-synuclein. Neuron, 79, 1044-1066.

[6] Tardiff, Daniel F, (2013) Yeast reveal a “druggable” Rsp5/Nedd4 network that ameliorates alpha-synuclein toxicity in neurons. Science, 1-8.

[7] Chung, Chee Yeun, (2013) Identification and rescue of alpha-synuclein toxicity in Parkinson patient-derived neurons. Science, 1-8.

[8] Fearer, Matt, (2013) Yeast, human stem cells drive discovery of new Parkinson’s disease drug targets. Whitehead Institute http://wi.mit.edu/news/archive/2013/yeast-human-stem-cells-drive-discovery-new-parkinson-s-disease-drug-targets

[9] Khurana, Vikram, Lindquist, Susan, (2010) Modelling neurodegeneration in Saccharomyces cerevisiae: why cook with baker’s yeast. Nature opinion, 11, 436-449.