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Liquid\u2013liquid 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 \u03b1\u2010synuclein with tau and its consequences on tau LLPS. We find \u03b1\u2010synuclein to have a low propensity for both, self\u2010coacervation and RNA\u2010mediated LLPS at pH\u00a07.4. However, full\u2010length but not carboxy\u2010terminally truncated \u03b1\u2010synuclein efficiently partitions into tau\/RNA droplets. We further demonstrate that Cdk2\u2010phosphorylation promotes the concentration of tau into RNA\u2010induced droplets, but at the same time decreases the amount of \u03b1\u2010synuclein inside the droplets. NMR spectroscopy reveals that the interaction of the carboxy\u2010terminal domain of \u03b1\u2010synuclein with the proline\u2010rich region P2 of tau is required for the recruitment of \u03b1\u2010synuclein into tau droplets. The combined data suggest that the concentration of \u03b1\u2010synuclein into tau\u2010associated condensates can contribute to synergistic aSyn\/tau pathologies.<\/jats:p>","DOI":"10.1002\/pro.4025","type":"journal-article","created":{"date-parts":[[2021,1,16]],"date-time":"2021-01-16T03:16:55Z","timestamp":1610767015000},"page":"1326-1336","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["Interplay between tau and \u03b1\u2010synuclein liquid\u2013liquid phase separation"],"prefix":"10.1002","volume":"30","author":[{"given":"Anna","family":"Siegert","sequence":"first","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE)  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Rankovic","sequence":"additional","affiliation":[{"name":"Department for NMR\u2010based Structural Biology Max Planck Institute for Biophysical Chemistry  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