See-through 'MitoFish' opens a new window on brain diseases

December 5, 2012, Technical University Munich
This is a confocal image of a zebrafish head showing labeling of sensory axon membranes (yellow), mitochondria (cyan), and autofluorescence (red). Credit: Image: Leanne Godinho and Thomas Misgeld, TU Muenchen

German scientists have demonstrated a new way to investigate mechanisms at work in Alzheimer's and other neurodegenerative diseases, which also could prove useful in the search for effective drugs. For new insights, they turned to the zebrafish, which is transparent in the early stages of its life. The researchers developed a transgenic variety, the "MitoFish," that enables them to see – within individual neurons of living animals – how brain diseases disturb the transport of mitochondria, the power plants of the cell.

Neurodegenerative diseases such as Alzheimer's, Parkinson's, ALS (), and MS (multiple sclerosis) are quite different in their effects on patients' cognitive and , behavior, and prognosis. Yet on the level of individual neurons, common mechanisms can be observed that either cause or accompany nerve degeneration in a number of different diseases. One of these is a disturbance in the transport of mitochondria, that play several vital roles in the life of a cell—above all, delivering energy where it is needed. And in a neuron, an extremely power-hungry cell, that means moving mitochondria all the way down its longest extension, the axon. Studying mitochondria transport in other animal models of neurodegenerative disease, particularly in mice, has been revealing. But the MitoFish model opens up new possibilities.

This is a confocal image of a single zebrafish sensory neuron with labeled membrane (red) and mitochondria (green). Credit: Image: Gabriela Plucinska, TU Muenchen

The new model was jointly developed in the labs of Prof. Thomas Misgeld of the Technische Universität München (TUM) and Dr. Bettina Schmid, a senior scientist of the German Center for Neurodegenerative Diseases (DZNE) based at the institute of LMU Prof. Christian Haass. "This collaboration has provided a system," Misgeld says, "with which we can try to understand the traffic rules or the life cycle of a given organelle, in this case mitochondria, in the context of a nerve cell that's existing in its physiological environment, where it is developing and changing. Most of these things we don't understand well enough to model them in another setting, so we have the organism do it for us."

The MitoFish is both readily manipulated, enabling researchers to pose specific questions, and literally transparent—allowing non-invasive in vivo observation of changes relevant to disease processes. It is possible to image a whole, living neuron over time and to follow the movements of mitochondria within it. "The is an established genetic model," Schmid explains, "which means you can bring foreign genes or certain proteins into a fish to test hypotheses about basic biology, disease mechanisms, or potential therapies. And because the early embryo is transparent, you can label specific with a fluorescent protein and then look at them in an intact, living animal."

This is a wide-field image of a zebrafish tail showing labeling of sensory axon membranes (green) and mitochondria (cyan). Credit: Image: Dominik Paquet, LMU Munich

The researchers stress that this new window into the could not have been opened without combining complementary expertise: from Misgeld's lab, imaging and analysis focused on organelle dynamics; and from Schmid's lab, development of transgenic zebrafish models that are stable enough for long-term study. The first authors of the team's report in the Journal of Neuroscience are Gabriela Plucinska (TUM) and Dominik Paquet (DZNE). The collaboration leaders are linked through participation in the newly established Excellence Cluster SyNergy (Munich Cluster for Systems Neurology), as well as in the DZNE and the Excellence Cluster CIPSM.

"Just talking to each other," Misgeld recalls, "we realized that this would be a perfect match—that she would have situations in which the kind of trafficking question I wanted to look at could be of high relevance, and that she had all the tools we would need to carry this forward."

The driving force, they emphasize, is to understand more about Alzheimer's and other to help steer the search for therapies in the right direction. "We need to understand how the machine works before we can operate it," Schmid says, "and modern biology is so technically advanced that no lab can be cutting-edge across the whole range of needed expertise."

Explore further: Observations refute widely held view on causal mechanism in amyotrophic lateral sclerosis

More information: Gabriela Plucińska, Dominik Paquet, Alexander Hruscha, Leanne Godinho, Christian Haass, Bettina Schmid, and Thomas Misgeld. In Vivo Imaging of Disease-Related Mitochondrial Dynamics in a Vertebrate Model System. The Journal of Neuroscience, 32(46):16203-16212. DOI:10.1523/JNEUROSCI.1327-12.2012

Related Stories

Observations refute widely held view on causal mechanism in amyotrophic lateral sclerosis

February 29, 2012
In science, refuting a hypothesis can be as significant as proving one, all the more so in research aimed at elucidating how diseases proceed with a view toward preventing, treating, or curing them. Such a discovery can save ...

Molecular knock-out alleviates Alzheimer's symptoms in mice

November 30, 2012
Researchers at the German Center for Neurodegenerative Diseases (DZNE) and the University Medical Center Göttingen (UMG) have identified an enzyme as a possible target for the treatment of Alzheimer's disease. The protein ...

Why do neurons die in Parkinson's disease?

November 10, 2011
Current thinking about Parkinson's disease is that it's a disorder of mitochondria, the energy-producing organelles inside cells, causing neurons in the brain's substantia nigra to die or become impaired. A study from Children's ...

Recommended for you

Research reveals atomic-level changes in ALS-linked protein

January 18, 2018
For the first time, researchers have described atom-by-atom changes in a family of proteins linked to amyotrophic lateral sclerosis (ALS), a group of brain disorders known as frontotemporal dementia and degenerative diseases ...

Fragile X finding shows normal neurons that interact poorly

January 18, 2018
Neurons in mice afflicted with the genetic defect that causes Fragile X syndrome (FXS) appear similar to those in healthy mice, but these neurons fail to interact normally, resulting in the long-known cognitive impairments, ...

How your brain remembers what you had for dinner last night

January 17, 2018
Confirming earlier computational models, researchers at University of California San Diego and UC San Diego School of Medicine, with colleagues in Arizona and Louisiana, report that episodic memories are encoded in the hippocampus ...

Recording a thought's fleeting trip through the brain

January 17, 2018
University of California, Berkeley neuroscientists have tracked the progress of a thought through the brain, showing clearly how the prefrontal cortex at the front of the brain coordinates activity to help us act in response ...

Midbrain 'start neurons' control whether we walk or run

January 17, 2018
Locomotion comprises the most fundamental movements we perform. It is a complex sequence from initiating the first step, to stopping when we reach our goal. At the same time, locomotion is executed at different speeds to ...

Miles Davis is not Mozart: The brains of jazz and classical pianists work differently

January 16, 2018
Keith Jarret, world-famous jazz pianist, once answered in an interview when asked if he would ever be interested in doing a concert where he would play both jazz and classical music: "No, that's hilarious. [...] It's like ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.