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Neurodegenerative conditions like Alzheimer’s, Parkinson’s and prion disease result from the misfolding and aggregation of key neuronal proteins. In fact, the striking loss of cognitive and motor abilities in these age-related illnesses is frequently linked to the appearance of abnormal protein deposits in neurons. However, the presence of plaques and tangles in elderly brains is not a precondition for neurodegeneration. Rather, neuronal damage is triggered by small precursors of these rogue proteins decades before brain deposits and clinical symptoms become evident.

Our research has two continuing goals:

  1. understanding the cellular and molecular mechanisms by which misfolded protein oligomers induce early neurotoxicity in vivo
  2. transforming this information into novel drug screening methodologies to identify anti-neurodegeneration compounds

To pursue these goals, we employ cell biological, biochemical and behavioral approaches in genetically and pharmacologically manipulated zebrafish embryos. These small vertebrates offer key experimental advantages, such as their external development and optical clarity, which allow for high resolution imaging of physiological processes in neurons.

Of special interest to our lab is the involvement of the cellular prion protein (PrPC) as a common receptor for various neurotoxic species in the brain, including amyloid β (aβ), α-synuclein and its own misfolded isoform, PrPSc. This intriguing role of PrPC as a broad transducer of neurotoxicity relies on its physiological ability to elicit complex intracellular signals. Therefore, many of our efforts are aimed at analyzing how PrP modulates molecular pathways and cellular events in health and disease.

The consistent lack of overt phenotypes in mice devoid of PrPC prompted our laboratory to address this question using zebrafish. Upon identifying fish PrPs and analyzing embryonic loss- and gain-of-function phenotypes, we showed that PrPC modulates cell-cell communication, either by promoting cell-contact formation through homophilic interactions, or by controlling the cell surface exposure of adhesion molecules via Src family kinase-dependent (SFK) phosphorylation. The latter mechanism is very relevant to Alzheimer’s neurodegeneration, as it also explains the toxic overactivation of mammalian glutamate receptors triggered by aβ oligomers.

Currently, our projects center around the following topics:

  • The complex roles of PrPC- and SFK-associated pathways during early morphogenesis and neural development, their genetic redundancy and compensatory mechanisms, maternal and zygotic gene functions.
  • Neurotoxic pathways induced by amyloids in vivo and their connection to the PrPC/SFK-mediated control of neuroreceptor and adhesion molecule activity.
  • Spatiotemporal dynamics of amyloid aggregation in the nervous system, their cellular uptake and processing.
  • Development of embryo-based neurotoxicity reporter assays to screen for anti-neurodegeneration drugs.

Our laboratory is equipped with state-of-the-art instrumentation, including micromanipulation and microinjection stations for the generation of transgenic and CRISPR-Cas mutant fish, optical sectioning and high resolution fluorescence confocal microscopes, systems for DNA and protein detection and analysis, molecular biology and bioinformatic resources, an automated behavioral tracking device and a dedicated zebrafish facility housing 3000 adult wildtype, mutant and transgenic animals.