Investigations into the phase separation and nuclear role of tau.

Abstract

Tau is a microtubule-associated protein and pathological hallmark of Alzheimer's disease (AD), most infamous for becoming hyperphosphorylated and fibrilizing into neurofibrillary tangles (NFTs). Beyond this role, mounting evidence suggests that tau localizes into the nucleus and plays unknown roles in DNA protection and heterochromatin regulation. Intriguingly, frontotemporal dementia mutants (P301L) of tau show loss of genetically silent heterochromatin clusters. This has been associated with aberrant expression of heterochromatic genes and in other studies, of transposable element activation in AD patient brain tissue. Similar effects of heterochromatin relaxation and gene dysregulation have been observed in tau knockouts, suggesting that loss of tau is pathologically relevant. Recent literature showed that tau undergoes liquid-liquid phase separation (LLPS). Studies have not fully described the functional role of nuclear tau in gene regulation, and whether this involves LLPS. My work demonstrates that tau has an intrinsic ability to phase separate with, compact, and oligomerize chromatin, likely through its DNA-binding domain, and this is regulated by phosphorylation. In addition, tau phase separates with heterochromatin protein 1α (HP1α), an essential heterochromatin constituent, which may promote its partitioning into heterochromatin despite its lack of DNA-sequence specificity. These data imply a potential role for tau LLPS in the maintenance of chromatin compaction with aging.