Importance of Model Systems in Parkinson’s Research

“Science is organized knowledge. Wisdom is organized life.” Will Duran

“The most exciting phrase to hear in science, the one that heralds new discoveries, is not ‘Eureka!’ but ‘That’s funny…’” Isaac Asimov

Introduction:  The goal of this post is to highlight several experimental model systems that have effectively been used in Parkinson’s research.  We  have gained tremendous knowledge about all aspects of Parkinson’s from the use of model systems (Please note there are many publications that could have been included here by many different outstanding scientists; this is just a sampling of the strong science in the field of Parkinson’s disease).

The alpha-synuclein story in Parkinson’s: Alpha-synuclein is  a protein found in the brain that form aggregates (clumps of protein) called Lewy bodies.   Lewy bodies accumulate inside the substantia nigra region of the brain and they are toxic to the neurons and they no longer synthesize dopamine.   Part of the toxicity of alpha-synuclein-forming Lewy bodies is linked to mitochondria inhibition,  the little energy factories found in  our cells. This is just a sampling of alpha-synuclein in Parkinson’s (here is a PubMed search: http://www.ncbi.nlm.nih.gov/pubmed/?term=alpha-synuclein+Parkinson%27s ).

“Science is the process that takes us from confusion to understanding…” Brian Greene

The need for experimental model systems:  Scientists develop and use various experimental tools to answer their research questions. The ‘strength’ of the observation is usually dependent on the ‘quality’ of the experimental model system. Described here are four of many different experimental model systems: yeast; Caenorhabditis elegans (C. elegans); human, rat or mouse neuronal cells; and the mouse (or rat). Ultimately, scientists and physicians ‘translate’ this information for use in human clinical trials, which defines the phrase “bench-to-bedside”.

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“I never guess. It is a capital mistake to theorize before one has data. Insensibly one begins to twist facts to suit theories, instead of theories to suit facts.” Sir Arthur Conan Doyle, Author of Sherlock Holmes stories

Advancing our understanding of Parkinson’s using experimental model systems: You must remember a couple of things about science and research in general. Asking and answering one question usually leads to another question that needs to be answered. Typically, the next questions are more complex as the story unfolds. It is kind of like peeling an onion, you start taking off the top layer and you keep going; the more questions you answer the more layers you have to peel. Let’s go peel some onions.

Rising yeast in biology:  In our everyday lives,  baker’s yeast is used to make bread and alcoholic beverages like beer.  Yeast are single cell organisms, but like human cells they are eukaryotic (defined as “…cells that contain a distinct membrane-bound nucleus and by the occurrence of DNA transcription inside the nucleus and protein synthesis in the cytoplasm….” http://www.thefreedictionary.com/eukaryote ). Yeast are easy to culture and they share many similarities to human cells;  furthermore, genetic manipulation is relatively easy to do in yeast and offers a powerful tool for biomedical science. [Also see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213361/%5D

Use of yeast in Parkinson’s research Tardiff and others performed a really clever experiment, they expressed alpha-synuclein in yeast.  They found that yeast, just like human neuronal cells, got sick in the presence of excess amounts of alpha-synuclein.  They used the yeast expressing alpha-synuclein  and asked the following questions. Could a compound neutralize or reverse the alpha-synuclein-induced toxicity in yeast? Would this compound be able to restore normal function to the yeast?  They tested  ~190,000 compounds to see whether any of those would reverse the toxic effects and allow the yeast to rapidly grow again.  One lead compound evolved from this study, N-aryl benzimidazole (NAB).  NAB corrected the problem in yeast expressing alpha-synuclein. Using elegant genetics, they found that NAB activates a “trafficking” protein named Rsp5. The alpha-synuclein-induced toxicity  was inhibiting the function of Rsp5, which means that NAB reverses this effect. This sets the scene for new pathways to be explored for how Parkinson’s evolves, and presents a new strategy for exploring drugs to treat this disorder.
Tardiff DF, Jui NT, Khurana V, et al. Yeast reveal a “druggable” Rsp5/Nedd4 Network that Ameliorates α–Synuclein Toxicity in Neurons. Science (New York, NY). 2013;342(6161):979-983. doi:10.1126/science.1245321.

“Science is a way of thinking much more than it is a body of knowledge.” Carl Sagan

“Worm people” advancing science using C. elegans: C. elegans are non-parasitic soil nematodes that are free-living (…worms of the phylum Nematoda, having unsegmented cylindrical bodies often narrowing at each end, and including free-living species that are abundant in soil and water, and species that are parasites of plants and animals…” http://www.thefreedictionary.com/nematode ). C. elegans is a model organism due to its ability to be easily grown and manipulated genetically, which scientists use to advance complex biological principles.  [Also see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1855192/%5D

Use of worms in Parkinson’s research Advanced age is the greatest known risk factor for development of Parkinson’s.  Why this happens is not fully understood. Cooper and others proposed the following hypothesis: “…there are specific changes that take place during the aging process that make cells susceptible to disease-causing mutations that are well-tolerated at younger ages.” To begin to ‘test’ this hypothesis, they used genetics and C. elegans as a model system.  Worms containing mutations in the daf-2 gene live twice as long as control worms.  The researchers crossed  C. elegans models of Parkinson’s with daf-2 mutants.  Compared to the appropriate control worms, the Parkinson’s/daf-2 mutant worms had longer lifespan, protection of dopamine neurons, resistance to inflammatory stress, and decreased Lewy-body formation. This C. elegans genetics-aging study implies that slowing down the aging process is neuroprotective in Parkinson’s.
Jason F Cooper, Dylan J Dues, Katie K Spielbauer, Emily Machiela, Megan M Senchuk, and Jeremy M Van Raamsdonk. Delaying aging is neuroprotective in Parkinson’s disease: a genetic analysis in C. elegans models. npj Parkinson’s Disease (2015) 1, 15022; doi:10.1038/npjparkd.2015.22; published online 19 November 2015

“What we find changes who we become.” Peter Morville

Cells provide a cultivating environment to model tissues/organs:  Over the past several decades, many different types of cells have been grown in sterile plastic dishes; ranging from “primary” cell extracts obtained from different organs to “immortalized” cell types from various tumor types (i.e., cancer).  Cells grown in vitro (defined as “performed or taking place in a test tube, culture dish, or elsewhere outside a living organism” https://www.google.com/search?q=define+in+vitro&ie=utf-8&oe=utf-8) do not fully recapitulate the organ of origin; nonetheless, cell culture is a powerful model system to study both normal biological and abnormal pathological processes. [Also see http://www.biologyreference.com/Bl-Ce/Cell-Culture.html%5D

Use of neuronal cells in Parkinson’s research Proteins have unique three-dimensional shapes, which encode their biological activity.  Sometimes, proteins go bad and do things that are pathological like alpha-synuclein forming aggregates. Moree and others are testing a hypothesis that small molecules can be discovered that reverse such detrimental protein aggregation. They developed a novel screening technique to identify compounds that modulate protein conformation (which is way beyond the scope of this blog posting). They discovered a compound named BIOD303 as a novel conformational modulator of alpha-synuclein.Interestingly, these modulators reduced alpha-synuclein aggregation in an experimental neuronal cell model. This sort of study could (possibly one day) lead to a novel process for treating Parkinson’s by reversing alpha-synuclein aggregates.
Moree B, Yin G, Lázaro DF, et al. Small Molecules Detected by Second-Harmonic Generation Modulate the Conformation of Monomeric α-Synuclein and Reduce Its Aggregation in Cells. The Journal of Biological Chemistry. 2015;290(46):27582-27593. doi:10.1074/jbc.M114.636027.

“Science does not know its debt to imagination.” Ralph Waldo Emerson

The mouse (rat) provides a most important model system:  Our understanding of many human diseases (think cardiovascular, cancer, and yes, Parkinson’s) has been advanced using mice and rats as model systems. One reason why mice are used is the similarity of mouse and human genetics. Scientists have done amazing feats using mice including “gene knockout” where specific genes have been deleted or inactivated.  Another type of mouse genetically-derived is the “transgenic mice”, which usually express genes thought to promote human diseases.  Ultimately, a mouse (or rat) with a specific disease becomes a model or ‘stand-in’ for that same human disease or condition.  [Also see  http://emice.nci.nih.gov/aam%5D

Use of rats in Parkinson’s researchVolakakis and others studied how alpha-synuclein promotes changes in dopamine-producing neurons. They found that alpha-synuclein alters gene expression and that a transcription factor (a protein that binds to specific DNA sequences that modulates the genetic information being transcribed from DNA to messenger RNA) known as Nurr1 helps resist these effects. They found that nuclear substances that bind to Nurr1’s partner retinoid X receptor (RXR) also had a neuroprotective role. Their results clearly highlight Nurr1’s neuroprotective role against alpha-synuclein-induced changes in dopamine-producing neurons. Furthermore, their results imply that RXR ligands have therapeutic potential in Parkinson’s.
Volakakis N, Tiklova K, Decressac M, Papathanou M, Mattsson B, Gillberg L, Nobre A, Björklund A, Perlmann T. Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression. J Neurosci. 2015 Oct 21;35(42):14370-85. doi: 10.1523/JNEUROSCI.1155-15.2015. PMID:26490873

“Barry L. Jacobs and colleagues from the neuroscience program at Princeton University showed that when mice ran every day on an exercise wheel, they developed more brain cells and they learned faster than sedentary controls. I believe in mice.”  Bernd Heinrich

From bench-to-bedside: The four papers described here represent the tip-of-the-iceberg in Parkinson’s research. As with any basic science study, the next step, the next few years are key to developing/advancing/evaluating these questions and getting answers. I am optimistic that new compounds, new treatment strategies, and further understanding of Parkinson’s are coming in the near future. It just will take time, so we must remain patient while all of their research endeavors progress.

“From the standpoint of daily life, however, there is one thing we do know: that we are here for the sake of each other – above all for those upon whose smile and well-being our own happiness depends, and also for the countless unknown souls with whose fate we are connected by a bond of sympathy. Many times a day I realize how much my own outer and inner life is built upon the labors of my fellow men, both living and dead, and how earnestly I must exert myself in order to give in return as much as I have received.” Albert Einstein

Cover photo credit: http://www.boredpanda.com/beautiful-winter-photos/

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