Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Calculating Gene and Protein Connections in a Parkinson’s Model

Researchers created an algorithm that meshes existing data to produce a clearer flow chart of how cells respond to stimuli. Using this new method, Whitehead Institute and MIT scientists have analyzed alpha-synuclein toxicity to identify genes and pathways that affect cell survival. Misfolded alpha-synuclein protein is a hallmark of Parkinson’s.

Researchers have created an algorithm that meshes existing data to produce a clearer step-by-step flow chart of how cells respond to stimuli. Using this new method, Whitehead Institute and Massachusetts Institute of Technology scientists have analyzed alpha-synuclein toxicity to identify genes and pathways that can affect cell survival. Misfolded copies of the alpha-synuclein protein in brain cells are a hallmark of Parkinson’s disease.

RELEVANCE: Until now, data on gene expression and protein production have not been consistently analyzed together, leaving gaps in researchers’ understanding of how various genes and proteins interact to form a cell’s response to a stimulus. This new method could speed the development of therapies for a variety of diseases, including Parkinson’s disease.

A novel approach to analyzing cellular data is yielding new understanding of Parkinson’s disease’s destructive pathways.

Whitehead Institute and Massachusetts Institute of Technology (MIT) scientists have employed this new computational technique to analyze alpha-synuclein, a mysterious protein that is associated with Parkinson’s disease.

Cells are constantly adapting to various stimuli, including changes in their environment and mutations, through an intricate web of molecular interactions. Knowledge of these changes is crucial for developing new treatments for diseases. To decipher how a cell responds to various stimuli, laboratories worldwide have been turning to new technologies that produce vast amounts of data. Such data typically exists in two major forms: genetic screen data (the results from deleting a gene from a cell’s genome and seeing what observable traits appear in the cell) and information on the cellular levels of messenger RNA (mRNA, which is the template for proteins).

Historically, these two types of data have largely been analyzed independently of each other, revealing only glimpses of the cell’s internal workings. Each type of data is actually biased toward identifying different aspects of cellular response, something that researchers had not realized until now. However, the new algorithm, known as ResponseNet, exploits these biases and allows for combined analysis.

In this combined analysis, both data types are integrated with molecular interactions data into a diagram that connects the experimentally identified proteins and genes. While this typically results in an extraordinarily complicated diagram, sometimes jokingly referred to as a “hairball”, ResponseNet is designed to whittle the hairball down to the most probable pathways connecting various genes and proteins.

Esti Yeger-Lotem, a postdoctoral researcher in the laboratories of Whitehead Member Susan Lindquist and of Ernest Fraenkel at MIT’s Biological Engineering department and co-author of the Nature Genetics article, says that by analyzing those probable pathways, a systems view of the cellular response emerges. “This allows for a more complete understanding of cellular response and can reveal hidden components of the response that may be targeted by drugs,” she says.

According to Laura Riva, a postdoctoral researcher in MIT’s biological engineering department and one of the designers of the algorithm, ResponseNet is potentially very useful for researchers.

“It is a powerful approach for interpreting experimental data because it can efficiently analyze tens of thousands of nodes and interactions,” says Riva, who is also a co-author on the article. “The output of ResponseNet is a sparse network connecting some of the genetic data to some of the transcriptional data via intermediate proteins. Biologists can look at the network and understand which pathways are perturbed, and they can use it to generate testable hypotheses.”

To demonstrate ResponseNet’s capabilities, Yeger-Lotem entered the data from screens of 5,500 yeast strains (Saccharomyces cerevisiae). These strains are based on a yeast model that creates large amounts of the protein alpha-synuclein, thereby mimicking the toxic effects of alpha-synuclein accumulation in Parkinson’s disease patients’ brain cells.

Ernest Fraenkel, Assistant Professor of Biological Engineering at MIT, says that the alpha-synuclein data are an excellent test case for the algorithm, which has lead to new insights from existing data.

“The connection between alpha-synuclein and Parkinson’s disease is enigmatic,” says Fraenkel. “We have wonderful data from the yeast model, but despite this richness of data, so little is known about what alpha-synuclein really does in the cell.”

Using these data, ResponseNet identified several links between alpha-synuclein toxicity and basic cell processes, including those used to recycle proteins and to usher the cell through its normal life cycle.

Surprisingly, ResponseNet also tied alpha-synuclein toxicity to a highly-conserved pathway targeted by cholesterol-lowering statin drugs and another pathway targeted by the immunosuppressing drug rapamycin.

To confirm ResponseNet’s links and to test how these two pathways could affect alpha-synuclein toxicity, researchers added either rapamycin or the statin lovastatin to yeast model cultures. When the researchers added a low dose of rapamycin to the yeast model, the drug was toxic to the yeast. When lovastatin was added, the yeast reduced their growth rate, an indicator that the yeast had gotten sicker. However, when researchers added the molecule ubiquinone (also known as coenzyme Q10 or CoQ10), which is farther downstream in the statin network and possibly undersynthesized in alpha-synuclein-containing yeast, ubiquinone modestly suppressed alpha-synuclein toxicity.

All of these results validated the hypotheses based on ResponseNet’s network.

“ResponseNet provides a wealth of new information,” says Lindquist, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. “Some of the things we have found offer a promise to speed the development of new therapeutic strategies for Parkinson’s disease. For the sake of the patients involved, let’s hope they hold true in a human brain.”

Ernest Fraenkel is the Eugene Bell Assistant Professor of biological engineering at Massachusetts Institute of Technology.

Susan Lindquist’s primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology.

Full Citation:
"Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity"

Nature Genetics, online February 22, 2009

Esti Yeger-Lotem (1,2,8), Laura Riva (1,8), Linhui Julie Su (2) Aaron D Gitler (2,7), Anil G. Cashikar (2,7), Oliver D King (2,7), Pavan K Auluck (2,3), Melissa L Geddie (2), Julie S Valastyan (2,4), David R Karger (5), Susan Lindquist (2,6) & Ernest Fraenkel (1,5)

1. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
2. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
3. Departments of Pathology and Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, and Harvard Medical School, Boston, Massachusetts 02115, USA.
4. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
5. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
6. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
7. Present addresses: Department of Cell and Developmental Biology, The University of Pennsylvania, Philadelphia, Pennsylvania, USA (A.D.G.), Medical College of Georgia, Augusta, Georgia, USA (A.G.C.) and Boston Biomedical Research Institute, Watertown, Massachusetts, USA (O.D.K.).

8. These authors contributed equally to this work.

Nicole Giese | Newswise Science News
Further information:

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>