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.


About us

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.

In particular working on the project:
Janine Hochmair (PhD student @DZNE Berlin),
Christian Exener (PhD student @Uni Hamburg),
Sven Falke (Project leader @Uni Hamburg)


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.

Contact:
Universität Hamburg
Institut für Biochemie und Molekularbiologie
Martin-Luther-King-Platz 6
20146 Hamburg
Phone: : +49 40 42838-6069 (Uni) / +49 40 8998-4744 (DESY)
Christian.Betzel@uni-hamburg.de


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 2011 Eckhard Mandelkow 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 (DZNE)
Ludwig-Erhard-Allee 2
53175 Bonn
mandelkow@mpasmb.desy.de
+49 228 43302-630


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.


Contact:
German Center for Neurodegenerative Diseases (DZNE)
c/o Charite Universitaetsmedizin Berlin
Chariteplatz 1, 10117 Berlin
Phone: +49 30 450539834
susanne.wegmann@dzne.de


Publications

Ukmar-Godec T, Wegmann S, Zweckstetter M.
Biomolecular condensation of the microtubule-associated protein tau. Semin Cell Dev Biol. 2019 Jul 4. pii: S1084-9521(18)30199-X.
doi: 10.1016/j.semcdb.2019.06.007.