TY  - JOUR
AU  - Prince, Prabhu Rajaiah
AU  - Hochmair, Janine
AU  - Brognaro, Hévila
AU  - Gevorgyan, Susanna
AU  - Franck, Maximilian
AU  - Schubert, Robin
AU  - Lorenzen, Kristina
AU  - Yazici, Selin
AU  - Mandelkow, Eckhard
AU  - Wegmann, Susanne
AU  - Betzel, Christian
TI  - Initiation and modulation of Tau protein phase separation by the drug suramin.
JO  - Scientific reports
VL  - 13
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DZNE-2023-00340
SP  - 3963
PY  - 2023
N1  - CC BY
AB  - Tau is an intrinsically disordered neuronal protein in the central nervous system. Aggregated Tau is the main component of neurofibrillary tangles observed in Alzheimer's disease. In vitro, Tau aggregation can be triggered by polyanionic co-factors, like RNA or heparin. At different concentration ratios, the same polyanions can induce Tau condensates via liquid-liquid phase separation (LLPS), which over time develop pathological aggregation seeding potential. Data obtained by time resolved Dynamic Light Scattering experiments (trDLS), light and electron microscopy show that intermolecular electrostatic interactions between Tau and the negatively charged drug suramin induce Tau condensation and compete with the interactions driving and stabilizing the formation of Tau:heparin and Tau:RNA coacervates, thus, reducing their potential to induce cellular Tau aggregation. Tau:suramin condensates do not seed Tau aggregation in a HEK cell model for Tau aggregation, even after extended incubation. These observations indicate that electrostatically driven Tau condensation can occur without pathological aggregation when initiated by small anionic molecules. Our results provide a novel avenue for therapeutic intervention of aberrant Tau phase separation, utilizing small anionic compounds.
KW  - Humans
KW  - tau Proteins: metabolism
KW  - Suramin: pharmacology
KW  - Alzheimer Disease: metabolism
KW  - Heparin
KW  - RNA: metabolism
KW  - tau Proteins (NLM Chemicals)
KW  - Suramin (NLM Chemicals)
KW  - Heparin (NLM Chemicals)
KW  - RNA (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36894559
C2  - pmc:PMC9997437
DO  - DOI:10.1038/s41598-023-29846-9
UR  - https://pub.dzne.de/record/256516
ER  -