Acetylation Disfavors Tau Phase Separation

• Published in: International journal of molecular sciences Vol. 19; no. 5; p. 1360
• Main Authors: Ferreon, Josephine C, Jain, Antrix, Choi, Kyoung-Jae, Tsoi, Phoebe S, MacKenzie, Kevin R, Jung, Sung Yun, Ferreon, Allan Chris
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.05.2018; MDPI
• Subjects: Acetylation; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloidogenesis; Biocompatibility; Chromatin; Deoxyribonucleic acid; DNA; DNA-binding protein; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Event-related potentials; FUS protein; Heparin; Heparin - chemistry; Histone acetyltransferase; Humans; intrinsically disordered protein; Intrinsically Disordered Proteins - genetics; Intrinsically Disordered Proteins - metabolism; Liquid-Liquid Extraction; membrane-less organelle; Microtubules - genetics; Microtubules - metabolism; neurodegenerative disease; p300 HAT acetylation; p300-CBP Transcription Factors - genetics; p300-CBP Transcription Factors - metabolism; Phase separation; Phosphorylation; post-translational modification; protein aggregation; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - metabolism; Proteins; Sarcoma; Tau fibrillation; Tau protein; tau Proteins - chemistry; tau Proteins - genetics; tau Proteins - metabolism; intrinsically disordered protein; neurodegenerative disease; p300 HAT acetylation; protein aggregation; Tau fibrillation; post-translational modification; membrane-less organelle
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19051360

Neuropathological aggregates of the intrinsically disordered microtubule-associated protein Tau are hallmarks of Alzheimer's disease, with decades of research devoted to studying the protein's aggregation properties both in vitro and in vivo. Recent demonstrations that Tau is capable of undergoing liquid-liquid phase separation (LLPS) reveal the possibility that protein-enriched phase separated compartments could serve as initiation sites for Tau aggregation, as shown for other amyloidogenic proteins, such as the Fused in Sarcoma protein (FUS) and TAR DNA-binding protein-43 (TDP-43). Although truncation, mutation, and hyperphosphorylation have been shown to enhance Tau LLPS and aggregation, the effect of hyperacetylation on Tau aggregation remains unclear. Here, we investigate how the acetylation of Tau affects its potential to undergo phase separation and aggregation. Our data show that the hyperacetylation of Tau by p300 histone acetyltransferase (HAT) disfavors LLPS, inhibits heparin-induced aggregation, and impedes access to LLPS-initiated microtubule assembly. We propose that Tau acetylation prevents the toxic effects of LLPS-dependent aggregation but, nevertheless, contributes to Tau loss-of-function pathology by inhibiting Tau LLPS-mediated microtubule assembly.