Phosphorylation regulates tau's phase separation behavior and interactions with chromatin

Area of Science:

• Biophysics
• Molecular Biology
• Neuroscience

Background:

• Tau protein is primarily known for its role in neurofibrillary tangles (NFTs) in Alzheimer's disease.
• Emerging evidence indicates tau's presence and function within the cell nucleus, potentially involving DNA protection and heterochromatin regulation.
• The precise molecular mechanisms of nuclear tau interactions remain largely unknown.

Purpose of the Study:

• To investigate the biophysical mechanisms by which tau interacts with nuclear components like DNA and chromatin.
• To elucidate the role of tau in chromatin organization and DNA accessibility.
• To determine the impact of tau phosphorylation on its nuclear interactions and phase separation properties.

Main Methods:

• In vitro biophysical experiments.
• Liquid-liquid phase separation (LLPS) assays with DNA, mononucleosomes, and nucleosome arrays.
• DNA digestion assays to assess DNA protection.
• Analysis of tau's interaction with chromatin under varying salt concentrations.
• Co-localization studies with phosphorylated HP1α.

Main Results:

• Tau undergoes LLPS with DNA, mononucleosomes, and nucleosome arrays under low salt conditions.
• Low tau concentrations induce chromatin compaction and protect DNA from enzymatic digestion.
• Tau exhibits strong, reversible interactions with nucleosome arrays at physiological salt concentrations, driven by DNA binding.
• Tau co-localizes with HP1α-containing heterochromatin droplets.
• Aberrant tau hyperphosphorylation disrupts tau-mediated LLPS and chromatin interactions.

Conclusions:

• Tau can directly modulate DNA and chromatin accessibility through LLPS and direct binding.
• These biophysical properties suggest a novel nuclear role for tau in genome regulation.
• Disruption of tau's nuclear interactions due to hyperphosphorylation may contribute to the nuclear pathology observed in tauopathies like Alzheimer's disease.