TY  - JOUR
AU  - Hochmair, Janine
AU  - Exner, Christian
AU  - Franck, Maximilian
AU  - Dominguez-Baquero, Alvaro
AU  - Diez, Lisa
AU  - Brognaro, Hévila
AU  - Kraushar, Matthew L
AU  - Mielke, Thorsten
AU  - Radbruch, Helena
AU  - Kaniyappan, Senthilvelrajan
AU  - Falke, Sven
AU  - Mandelkow, Eckhard
AU  - Betzel, Christian
AU  - Wegmann, Susanne
TI  - Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates
JO  - The EMBO journal
VL  - 41
IS  - 11
SN  - 0261-4189
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2022-00525
SP  - e108882
PY  - 2022
N1  - (CC BY-NC-ND)
AB  - 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.
KW  - Humans
KW  - Microtubules: metabolism
KW  - Neurodegenerative Diseases: metabolism
KW  - Neurons: metabolism
KW  - Protein Binding
KW  - RNA: metabolism
KW  - tau Proteins: metabolism
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9156969
C6  - pmid:35298090
DO  - DOI:10.15252/embj.2021108882
UR  - https://pub.dzne.de/record/163787
ER  -