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Dominik Paquet
Laboratory for Neurodegenerative Diseases - LMU Munich
LMU, Schillerstr. 44, 80336 Munich
(+49-89) 2180-75 490
(+49-89) 2180-75 415


NEW: Learn more about Alzheimer research in zebrafish and see Dominik working at

DFG Science TV - Search for a Cure.


NEW: read about Dominik's work at SPIEGEL Online: Der neuronale Untergang (article only in german)


Neurodegenerative dementias belong to the most common forms of neurological diseases, more than 25 million people are affected worldwide, among them 1 million in Germany. Currently, no mechanism-based treatments are available. Since age is the major risk factor for these dementias, the number of patients will double until 2050, due to the increasing life expectancies of people around the world.
The neuropathology of Alzheimers disease, the most common form of dementia, is mainly characterized by the appearance of neurofibrillary tangles in neurons of the brain, as well as extracellular deposits of the Abeta peptide, called plaques. Tangles consist of filaments of a misfolded and posttranslationally modified form of the Tau-protein. Tangles are also a hallmark of other dementias, such as certain frontotemporal dementias. Dementias with Tau-pathology are therefore also termed Tauopathies.
Current dementia research focuses on the questions, which degenerative processes take place early in the diseased neurons, why the cells die, and how this processed could be halted. Animal models are essential tools to study these aspects of neurodegenerative diseases. Researchers mainly use transgenic animals, in which a mutated human gene that accelerates the disease in humans was introduced. Due to the relatively late onset of symptoms in existing transgenic mouse models and the fact that it is not well feasible to use these animals for in vivo imaging of disease progression or large scale drug development, there is an unmet need for alternative animal models.
Therefore, during the course of this project transgenic zebrafish were developed as a model of Tauopathies, which express a mutant form of the human Tau-protein and rapidly recapitulate major disease symptoms.

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An adult Zebrafish

Zebrafish are well suited for in vivo imaging due to the translucent body of the larvae. In addition, the small body size of the larvae allows performing large-scale drug development and in-vivo-validation approaches. In the Tau-transgenic zebrafish, the first pathologic alterations were visible after only a few hours: the human Tau-protein altered its folding and biochemical composition and was relocalized from neuronal projections to the cell body. Thereafter, first degenerative processes could be monitored, during which neurons died in the central nervous system of the transgenic fish.
This neurodegeneration, which is typically associated with Tauopathies, could be monitored in vivo under the microscope for several hours.

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2 day old zebrafish larvae still inside the eggshell

In addition, the transgenic animals formed neurofibrillary tangles after some weeks, another pathological hallmark of several dementias including Alzheimers disease. The results indicate that the Tau-transgenic animals recapitulate the most relevant symptoms of Tau-associated human dementias and therefore, the animals are well suited for Tauopathy research. Due to the rapidly occurring disease symptoms, the fish could also be used to test chemical compounds for their ability to modify disease symptoms. In this test, an inhibitor of the Tau-Kinase GSK3, which was newly developed by a pharmaceutical company, was able to highly reduce the pathologic alterations of the Tau protein. This inhibitor was more than twice as potent as previously published inhibitors. Interestingly, another chemically similar and in cell culture equally potent inhibitor was completely inactive in this in-vivo-test, presumably due to low uptake of the compound into the nervous system or rapid breakdown. This example shows the necessity for drug tests in living animals and the suitability of the fish system to rapidly perform these tests.

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Injection of plasmid DNA into zebrafish eggs

The experiments illustrate the usefulness of the new Tau-transgenic zebrafish to study early degenerative processes leading to neuronal death in dementias and also their abilities to identify new drug targets. As this is the first zebrafish model of Tau-associated dementias with disease symptoms worldwide, this work is an important contribution to current dementia research and drug identification approaches.










  • Paquet D, Bhat R, Sydow A, Mandelkow E, Berg S, Hellberg S, Faelting J, Distel M, Koester RW, Schmid B, Haass C (2009) A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J Clin Invest. 2009 May;119(5):1382-95. Epub 2009 Apr 13. NCBI Fulltext


  • Paquet D, Haass C (2009). Neurodegeneration live: Alzheimerforschung in transgenen Zebrafischen. BIOspektrum 06/2009 Article in german: Fulltext


  • Paquet D, Schmid B, Haass C (2009). Transgenic zebrafish as a novel animal model to study Tauopathies and other neurodegenerative disorders in vivo. Neurodegener Dis. 2010;7(1-3):99-102. Epub 2010 Feb 18. NCBI Fulltext

  • VanBebber F, Paquet D, Hruscha A, Schmid B, Haass C (2009). Methylene Blue fails to inhibit tau and Polyglutamine Protein dependent Toxicity in Zebrafish. Neurobiol Dis. 2010 Sep;39(3):265-71. Epub 2010 Apr 8. NCBI Fulltext


  • Fett M, Pilsl A, Paquet D, Haass C, Tatzelt J, Schmid B, Winklhofer K (2010). Parkin is protective against proteotoxic stress in a transgenic zebrafish model. PLoS One. 2010 Jul 30;5(7):e11783. NCBI Fulltext


  • Exner N, Treske B, Paquet D, Holmstrom K, Schiesling C, Gispert S, Carballo-Carbajal I, Berg D, Hoepken HH, Gasser T, Krueger R, Winklhofer KF, Vogel F, Reichert AS, Auburger G, Kahle PJ, Schmid B, Haass C. Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J Neurosci. 2007 Nov 7;27(45):12413-8 NCBI Fulltext




  • Scholarship by e-fellows.net for outstanding results in studies, internships, periods spent abroad and extracurricular activities.


  • Scholarship by Universitaet Bayern e.V. for outstanding results in studies, internships, periods spent abroad and extracurricular activities.













Postdoc at Marc Tessier-Lavigne's Lab, The Rockefeller University, New York

Contact Info

Dominik Paquet
...
Alumni
Neurobiology
Haass Lab