TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau

Abstract

Tau protein plays an important role in the biology of stress granules and in the stress response of neurons, but the nature of these biochemical interactions is not known. Here we show that the interaction of tau with RNA and the RNA binding protein TIA1 is sufficient to drive phase separation of tau at physiological concentrations, without the requirement for artificial crowding agents such as polyethylene glycol (PEG). We further show that phase separation of tau in the presence of RNA and TIA1 generates abundant tau oligomers. Prior studies indicate that recombinant tau readily forms oligomers and fibrils in vitro in the presence of polyanionic agents, including RNA, but the resulting tau aggregates are not particularly toxic. We discover that tau oligomers generated during copartitioning with TIA1 are significantly more toxic than tau aggregates generated by incubation with RNA alone or phase-separated tau complexes generated by incubation with artificial crowding agents. This pathway identifies a potentially important source for generation of toxic tau oligomers in tau-related neurodegenerative diseases. Our results also reveal a general principle that phase-separated RBP droplets provide a vehicle for coassortment of selected proteins. Tau selectively copartitions with TIA1 under physiological conditions, emphasizing the importance of TIA1 for tau biology. Other RBPs, such as G3BP1, are able to copartition with tau, but this happens only in the presence of crowding agents. This type of selective mixing might provide a basis through which membraneless organelles bring together functionally relevant proteins to promote particular biological activities.

Pathological tau drives ectopic nuclear speckle scaffold protein SRRM2 accumulation in neuron cytoplasm in Alzheimer’s disease

“…Recent studies of other nuclear speckle resident proteins revealed that the nuclear speckle resident RNA nucleases parn-1 /PARN and parn-2 /TOE1 play distinct roles in tau toxicity [ 15 ]. Contemporaneous work from other laboratories has also implicated RNA-binding proteins in tauopathy, including Musashi (MSI) and T-cell intracellular antigen 1 (TIA1); while they have divergent RNA-binding functions, both TIA1 and MSI co-localize with tau-containing cytoplasmic lesions and modulate tau aggregation and concomitant tauopathy phenotypes in model systems [ 30 – 33 ].…”

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

“…Tau LLPS is regulated by intermolecular electrostatic interactions [ 12 ] and post-translational modifications, such as phosphorylation [ 7 , 13 ] and acetylation [ 14 ]. The RNA and RNA binding protein TIA1 can also interact with tau to drive tau LLPS [ 15 ]. The C -terminal microtubule-binding repeats of tau are the aggregation-prone region [ 16 ], which are believed to facilitate tau aggregation and play a crucial role in the formation of neurofibrillary tangles in Alzheimer’s disease (AD).…”

Interplay of RNA-Binding Proteins and microRNAs in Neurodegenerative Diseases

“…RBM45 acts as a component of the spliceosome, and its splicing process is regulated by miR-4454 in response to insulin signaling in a cell type-dependent manner, although such regulation has been reported only in the prostate glands so far [163]. The direct interaction of tau with TIA1 in the presence of RNA promotes the phase separation of tau and the formation of toxic oligomeric tau [164]. TIA1 plays an important role in the translational silencing of Methyl CpG-binding protein 2 (MECP2), which is important for normal brain development and physiology, in combination with Pummilio1, which recruits miR-200a and -302c, while HuC, instead of TIA1, predominates in neurons, resulting in a switch to translational enhancement [165].…”