Analysis of the involvement of RNA-binding proteins in TAU-dependent neurodegeneration

TAU-dependent neurodegeneration encompasses a group of disorders, collectively known as tauopathies, characterized by the pathological accumulation of the TAU protein. TAU is a microtubule-associated protein that stabilizes neuronal microtubules, but emerging evidence indicates it also plays a role in RNA metabolism through interactions with RNA-binding proteins (RBPs). RBPs are essential for the regulation of mRNA transport, translation, and the formation of stress granules (SGs), which are critical for synaptic function and maintenance. We hypothesize that TAU pathology induces dysregulation of RBPs involved in RNA transport, the translation preinitiation complex (PIC), and SG formation, contributing to neurodegeneration. We observed that the expression of RBPs involved in RNA transport, PIC, and SG formation is increased in the hippocampus of both an adeno-associated virus AAV-TAU^P301L mouse model and 8 months old transgenic TAU^P301S mice, as well as in samples from patients with Alzheimer's disease (AD). This change in expression is evident at both mRNA and protein levels and, in some cases, is accompanied by alterations in their subcellular localization. Our results suggest that RBP dysregulation is a common mechanism in various tauopathies and may be related to impaired TAU functionality. Furthermore, the upregulation of RBPs may represent a compensatory mechanism in response to deficits in synaptic translation.