Tau <i>N</i>-Terminal Inserts Regulate Tau Liquid-Liquid Phase Separation and Condensates Maturation in a Neuronal Cell Model

• Main Authors: Chengchen Wu, Junyi Zhao, Qiuping Wu, Qiulong Tan, Qiong Liu, Shifeng Xiao
• Format: Article
• Language: English
• Published: MDPI AG 2021-09-01
• Series: International Journal of Molecular Sciences
• Subjects: liquid–liquid phase separation; tau isoforms; protein aggregation; p62 protein
• Online Access: https://www.mdpi.com/1422-0067/22/18/9728
• ISSN: 1661-6596; 1422-0067

The microtubule-associated protein tau can undergo liquid–liquid phase separation (LLPS) to form membraneless condensates in neurons, yet the underlying molecular mechanisms and functions of tau LLPS and tau droplets remain to be elucidated. The human brain contains mainly 6 tau isoforms with different numbers of microtubule-binding repeats (3R, 4R) and <i>N</i>-terminal inserts (0<i>N</i>, 1<i>N</i>, 2<i>N</i>). However, little is known about the role of <i>N</i>-terminal inserts. Here we observed the dynamics of three tau isoforms with different <i>N</i>-terminal inserts in live neuronal cell line HT22. We validated tau LLPS in cytoplasm and found that 2<i>N</i>-tau forms liquid-like, hollow-shell droplets. Tau condensates became smaller in 1<i>N</i>-tau comparing with 2<i>N</i>-tau, while no obvious tau accumulated dots were shown in 0<i>N</i>-tau. The absence of <i>N</i>-terminal inserts significantly affected condensate colocalization of tau and p62. The results reveal insights into the tau LLPS assembly mechanism and functional effects of <i>N</i>-terminal inserts in tau.