Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Transcription factor protein's role in cell death, neurodegeneration and schizophrenia

09.06.2006
Researchers at the University of Pennsylvania School of Medicine discovered that a protein called Elk-1 interacts with mitochondria, the energy storehouse of a cell, suggesting that this protein -– typically active in the nucleus -- could play a role in cell death and mitochondria-related diseases such as neurodegeneration and schizophrenia.

The neuron is a particular type of cell in the brain that is responsible for, among other tasks, learning and memory, cognitive function, and other higher order physiologies. The neuronal cell exhibits a complex structure where fine hair-like structures called dendrites receive signals from other neurons. These signals are transferred to the soma, or body, of the cell and result in neuronal responsiveness to stimulation.


Localization of Elk-1 protein in neuronal dendrites. Elk-1 appears in red. Credit: (Credit: Lindy Barrett, PhD and Jai Yoon Sul, PhD, University of Pennsylvania School of Medcine, and Nature Methods, June 2006)

The researchers found that mRNA (messenger RNA) and protein encoding Elk-1, a transcription factor, were localized in the dendrites of intact rodent neurons. "Transcription factors normally only function in the nucleus and to find a transcription factor in the dendrite is pretty unique," says senior author James Eberwine, Ph.D., professor of pharmacology. "These factors are proteins that bind to DNA and play a role in the regulation of gene expression by promoting transcription. Our lab and others showed that Elk-1 is present in the dendrites of nerve cells." Transcription is the process of translating the DNA code into protein.

Along with Eberwine, co-authors Lindy Barrett, Ph.D., a student from the Eberwine lab who was recently awarded her doctorate in philosophy; Philip Haydon, Ph.D., professor of neuroscience; Jai Yoon Sul, Ph.D., a postdoctoral fellow in the Haydon lab; and colleagues published their findings in the June issue of Nature Methods and a March issue of the Proceedings of the National Academy of Sciences.

In the series of experiments (described in the PNAS study) to discern the nature of Elk-1's role in the dendrite, the investigators first characterized some of the proteins with which Elk-1 interacts, and found that Elk-1 associates with mitochondria proteins. Mitochondria are distributed throughout cells, including in the dendrites, and are important in maintaining the energy stores and regulating viability and death of the cell.

The researchers then overexpressed Elk-1 in rat neurons to see if there was an effect on cell viability. "We thought that through interaction with Elk-1, the mitochondria would be able to regulate cell death," says Eberwine. "By overexpressing Elk-1, we found that we did decrease cell viability, achieving more cell death. Conversely, when we knock-down Elk-1 expression, the survivability of neurons increased, which indicates that Elk-1 plays a role in neuron viability."

Cell-death is a component of a number of psychiatric and neurological diseases such as schizophrenia and those that involve neurodegeneration. For many of these diseases dysfunction of the dendrite is also associated with the disease process. "Therefore, anything that impacts dendrite function might be associated with illness," surmises Eberwine. "The fact that Elk-1 RNA and protein are present in dendrites, and the fact that Elk-1 can modulate cell viability, potentially through the mitochondria, suggests that Elk-1 could play a role in these diseases perhaps through modulation of mitochondrial activity."

To more precisely understand the role of Elk-1 RNA in the dendrite, the researchers developed a method called phototransfection, which was described in their June Nature Methods paper, to focally introduce Elk-1 RNA into the dendrite. In this technique, a laser light beam is used to create small transient pores in the membrane of intact rat nerve cells, into which a known amount of RNA molecules are introduced by diffusion.

The introduction and translation of Elk-1 mRNA in dendrites by phototransfection also elicited cell death whereas introduction and translation of Elk-1 mRNA in the cell soma did not produce cell death. The Elk-1 proteins translated in the dendrites were transported to the nucleus and cell death depended on subsequent transcription. These results compliment and expand upon the PNAS study in which Elk-1's involvement in cell death and association with mitochondria were elucidated.

"This is the first formal proof that RNA can be translated and made into protein in an intact neuronal dendrite," explains Eberwine. "We have seen this with isolated dendrites before, but not in an intact cell."

In the mouse model, Elk-1 mRNA is being made into protein on ribosomes located at the periphery of the nerve cell in the dendrite. Protein is also being made in the cell body, but there may be a difference in the Elk-1 protein made in the cell body. "We speculate that the dendrite's environment comes into play, with kinases and phosphatases that modify the Elk-1 proteins made in the dendrite," explains Eberwine. "We suggest that there's a different phosphorylation signal on the protein made in the dendrite versus in the cell body.

"These studies highlight the importance of the dendritic environment in modifying proteins after they have been made," concludes Eberwine. "There is a clear link between the nucleus and mitochondria via Elk-1, and it's rapid. We don't know exactly what that is, but it's a very interesting signal in terms of neurodegeneration. These data provide intriguing new avenues for research, including determining the role of localized protein synthesis and protein modifications in dendrite-related pathologies, including Fragile X disease, schizophrenia and autism. It is likely that not only are particular proteins going to be important in these diseases, which has been proven by genetics, but also the environment in which they are synthesized."

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht Modern genetic sequencing tools give clearer picture of how corals are related
17.08.2017 | University of Washington

nachricht The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Gold shines through properties of nano biosensors

17.08.2017 | Physics and Astronomy

Greenland ice flow likely to speed up: New data assert glaciers move over sediment, which gets more slippery as it gets wetter

17.08.2017 | Earth Sciences

Mars 2020 mission to use smart methods to seek signs of past life

17.08.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>