Betzel/Mandelkow/Wegmann

Molecular and Cellular Determinants of Tau Protein Condensation into Dense Liquid Phases

The neuronal tau protein is involved in the regulation of the axonal microtubule skeletton in the brain. In neurodegenerative diseases such as Alzheimer’s disease (AD) and Frontotemporal dementia (FTD), tau becomes aberrantly phsophorylated, and aggregated tau accumulates in the neuronal soma. Phopshorylation is also involved in regulating tau’s binding to microtubules and other physiological functions. We and others recently found that tau can condensate into liquid phases and that this process is regulated by posttranslational modifications of tau: for example phosphorylation triggers, and acetylation inhibits tau LLPS. Furthermore, tau condensates can transition into aggregates with biological seeding potential, a process that could contribute to tau aggregation in the brain in the context of AD and tauopathies. In the framework of the SPP2191, we extend our previous findings and determine, which physiological and pathological conditions favor tau condensation and the transition into aggregation, both on the physicochemical and structural level in vitro as well as in the neuronal context using neuronal cultures and postmortem human brain tissue.


Current State of Research

We just finished to produce recombinant proteins and are currently testing the influence of kinase-dependent phosphorylation on tau LLPS in vitro (AG Wegmann), and running first SAXS experiments to determine structural changes that occur in tau condensates over time (AG Betzel). Cell and neuron experiments will start soon as well.


We are a multidisciplinary team that characterizes condensation processes of the neuronal Tau protein in vitro and in neurons. Our overall aim is to decipher the determinants that drive tau phase separation and the transition into aggregation, and to determine its relevance in neurobiology and tau-related proteinopathies.
The Wegmann Lab in Berlin determines how physiological and pathological tau phosphorylation influences tau LLPS, which other cellular components are involved, and decsribes the effects on cellular processes and neuronal health.
The Mandelkow Lab in Bonn studies which protein domains are involved, how FTD-mutations influence tau LLPS, and if compounds can be identified or developed that stop pathological but not physiological tau condensation.
In the Betzel Lab in Hamburg, state-of-the-art X-ray and light scattering techniques are used to describe structural transitions that occur in tau condensates; these studies aim to describe the liquid to gel to aggregate transition in tau condensates on the molecular and mesoscale level.


Eckhard Mandelkow studied physics in Braunschweig, New Orleans, and Hamburg, and received his doctoral degree at the Max-Planck-Institute for Medical Research in Heidelberg for X-ray analysis of the structure of tobacco mosaic virus. This was followed by postdoctoral training at Brandeis University, Waltham MA (structure of cytoskeletal proteins). In 1986 he moved to the Deutsches Elektronensynchrotron (DESY) in Hamburg, Germany, and worked as director at the Max-Planck-Unit for Structural  Molecular Biology, professor at Hamburg University, and scientific member of the Max-Planck-Society. His research focussed on structural molecular biology by X-rays using synchrotron radiation, image reconstruction in electron microscopy, cytoskeleton (microtubules, motor proteins), the structure, function, and aggregation of tau protein and protein kinases in Alzheimer disease, and the development of tau aggregation inhibitors. He is recipient of a 2010 Metlife Award, a 2011 Potamkin Award, and a 2013 Alzheimer’s Association Iqbal Life Time Achievement Award. In 2011 he joined the German Center for Neurodegenerative Diseases in Bonn (DZNE) as a Principal Investigator where his lab focusses on “Structural Principles of Neurodegeneration”.

Contact:
German Center for Neurodegenerative Diseases in Bonn (DZNE)
Ludwig-Erhard-Allee 2
53175 Bonn
eckhard.mandelkow@dzne.de
+49 228 43302-630