TIA1 regulates the generation and response to toxic tau oligomers

Abstract

RNA binding proteins (RBPs) are strongly linked to the pathophysiology of motor neuron diseases. Recent studies show that RBPs, such as TIA1, also contribute to the pathophysiology of tauopathy. RBPs co-localize with tau pathology, and reduction of TIA1 protects against tau-mediated neurodegeneration. The mechanism through which TIA1 reduction protects against tauopathy, and whether TIA1 modulates the propagation of tau, are unknown. Previous studies indicate that the protective effect of TIA1 depletion correlates with both the reduction of oligomeric tau and the reduction of pathological TIA1 positive tau inclusions. In the current report, we used a novel tau propagation approach to test whether TIA1 is required for producing toxic tau oligomers and whether TIA1 reduction would provide protection against the spread of these oligomers. The approach used young PS19 P301S tau mice at an age at which neurodegeneration would normally not yet occur and seeding oligomeric or fibrillar tau by injection into hippocampal CA1 region. We find that propagation of exogenous tau oligomers (but not fibrils) across the brain drives neurodegeneration in this model. We demonstrate that TIA1 reduction essentially brackets the pathophysiology of tau, being required for the production of tau oligomers, as well as regulating the response of neurons to propagated toxic tau oligomers. These results indicate that RNA binding proteins modulate the pathophysiology of tau at multiple levels and provide insights into possible therapeutic approaches to reduce the spread of neurodegeneration in tauopathy.

Modulating disease-relevant tau oligomeric strains by small molecules

“…A growing body of evidence suggests that tau plays a causal role in mediating neurodegeneration and is strongly correlated with cognitive decline in AD and related diseases ( 62 , 63 ). Tauopathies comprise a large group of age-related neurodegenerative diseases, characterized by predominant accumulation and deposition of pathological tau aggregates or in combination with other toxic amyloid aggregates ( 18 , 23 , 50 , 64 – 67 ). Recent evidence has suggested that the accumulation of tau is mediated through the spreading of misfolded tau seeds from cell-to-cell and from initial brain regions throughout the brain in a trans-synaptic pattern as the disease progresses, thus proposing a prion-like mechanism for tau protein to propagate the disease ( 19 , 68 , 69 ).…”

Stress granules and neurodegeneration

“…Late-stage pathology also exists, which is made up of insoluble RBPs or tau molecules that appear to be consolidated into relatively homogeneous pathological aggregates, in which associated proteins become excluded 56 . Studies using seeding and propagation (described below) suggest that tau pathology evolves in a manner similar to TDP43 pathology, proceeding through a SG intermediate 134 .…”

Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia

“…Other groups have shown that the propagated Tau oligomers lead to reduced long-term potentiation and increased short-term depression effect on cortical neurons, which has been partially blocked by the administration of oligomer-specific antibody [13,14]. Oligomers are the unstable species with neurotoxicity and inflammatory activity, which acts as a seed for further aggregation [13,15,16]. Mirbaha et al have evidenced that the small size and confirmation of Tau oligomers (mainly, trimer) are ideal for cellular uptake and propagation [17].…”