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  Interplay between tau and α‐synuclein liquid–liquid phase separation

Sieger, A., Rankovic, M., Favretto, F., Ukmar‐Godec, T., Strohäker, T., Becker, S., et al. (2021). Interplay between tau and α‐synuclein liquid–liquid phase separation. Protein Science, In Press. doi:10.1002/pro.4025.

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Sieger, A., Author
Rankovic, M.1, Author           
Favretto, F., Author
Ukmar‐Godec, T., Author
Strohäker, T.1, Author           
Becker, S.2, Author           
Zweckstetter, M.3, Author           
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society, ou_578571              
2Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
3Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: LLPS, phosphorylation, tau, truncation, α‐synuclein
 Abstract: In Parkinson's disease with dementia, up to 50% of patients develop a high number of tau‐containing neurofibrillary tangles. Tau‐based pathologies may thus act synergistically with the α‐synuclein pathology to confer a worse prognosis. A better understanding of the relationship between the two distinct pathologies is therefore required. Liquid–liquid phase separation (LLPS) of proteins has recently been shown to be important for protein aggregation involved in amyotrophic lateral sclerosis, whereas tau phase separation has been linked to Alzheimer's disease. We therefore investigated the interaction of α‐synuclein with tau and its consequences on tau LLPS. We find α‐synuclein to have a low propensity for both, self‐coacervation and RNA‐mediated LLPS at pH 7.4. However, full‐length but not carboxy‐terminally truncated α‐synuclein efficiently partitions into tau/RNA droplets. We further demonstrate that Cdk2‐phosphorylation promotes the concentration of tau into RNA‐induced droplets, but at the same time decreases the amount of α‐synuclein inside the droplets. NMR spectroscopy reveals that the interaction of the carboxy‐terminal domain of α‐synuclein with the proline‐rich region P2 of tau is required for the recruitment of α‐synuclein into tau droplets. The combined data suggest that the concentration of α‐synuclein into tau‐associated condensates can contribute to synergistic aSyn/tau pathologies.

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Language(s): eng - English
 Dates: 2021-01-15
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1002/pro.4025
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Title: Protein Science
Source Genre: Journal
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Pages: - Volume / Issue: - Sequence Number: In Press Start / End Page: - Identifier: -