Journal Article

DZNE-2022-00525

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates

Hochmair, J. (First author)DZNE* ; Exner, C. ; Franck, M.DZNE* ; Dominguez-Baquero, A.DZNE* ; Diez, L.DZNE* ; Brognaro, H. ; Kraushar, M. L. ; Mielke, T. ; Radbruch, H. ; Kaniyappan, S.DZNE* ; Falke, S. ; Mandelkow, E.DZNE* ; Betzel, C. ; Wegmann, S. (Last author)DZNE*

2022
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.15252/embj.2021108882

Abstract: Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, two conditions likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and to produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, their synergy enhances bundling and spatial arrangement of microtubules. We further show that different Tau condensates efficiently induce pathological Tau aggregates in cells, including accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations and a condensate-like density for nuclear-envelope Tau. These findings suggest that a complex interplay between interaction partners, post-translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding-competent Tau and lead to distinct cellular Tau accumulations.

Keyword(s): Humans (MeSH) ; Microtubules: metabolism (MeSH) ; Neurodegenerative Diseases: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Protein Binding (MeSH) ; RNA: metabolism (MeSH) ; tau Proteins: metabolism (MeSH)

Note: (CC BY-NC-ND)

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Contributing Institute(s):

1. Protein Actions in Neurodegeneration (AG Wegmann)
2. Structural Principles of Neurodegeneration (AG Mandelkow 1)
3. Cell and Animal Models of Neurodegeneration (AG Mandelkow 2)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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