Dept. of Pharmacology and Neurology, Boston University Medical Campus, Boston, MA, USA
RNA binding proteins (RBPs) increasingly appear to be important drivers of neurodegenerative diseases. TDP-43 occurs in about 50% of cases of sporadic Alzheimer’s disease (AD), and is the major pathology that accumulates in both Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia with TDP-43 (FTD-TDP). The ability of RNA binding proteins to cause disease is shown by the presence of mutations in many different RBPs (including TDP-43) that are associated with familial motor neuron diseases, such as ALS.
RBPs appear to cause disease because of their unique biology that controls the localization of mRNA in a cell through a process of reversible aggregation, mediated by low complexity, aggregation prone domains present in most RBPs. Studies with recombinant proteins show that these low complexity domains associate in a process termed liquid-liquid phase separation. The vulnerability to form pathology is highlighted by the tendency of these recombinant protein complexes to form amyloids that irreversibly aggregate in a process that is accelerated by disease linked mutations. In cells and neurons, these RBPs control RNA localization and RNA translation by forming RNA granules, including stress granules (SGs), which regulate which transcripts are translated into protein. We have recently discovered and demonstrated in vivo that somatodendritic localization of tau in disease functions to promote SG formation in neurons. Importantly, the association of tau with SGs promotes tau aggregation, while inhibiting SG formation delays tau-mediated neurodegeneration.
Using the PS19 P301S tau transgenic mouse line, we observe that reducing T cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival ce. The protection associated with TIA1 reduction includes increased binding of tau to microtubules, stabilization of microtubules, improved spatial working memory, and reduced synaptic and neuronal loss. Remarkably, this protection occurs despite increasing tau fibrils. In contrast, TIA1 reduction induces a corresponding decrease in soluble tau oligomers. Our data suggest that RBPs can direct the pathway of tau aggregation and the resulting neurodegeneration. These results also provide a striking example in which the accumulation of neurofibrillary tangles is dissociated from neurodegeneration, and identify inhibition of RBP aggregation as a compelling therapeutic strategy in tauopathies.