RNA binding proteins co-localize with small tau inclusions in tauopathy

Abstract

The development of insoluble, intracellular neurofibrillary tangles composed of the microtubule-associated protein tau is a defining feature of tauopathies, including Alzheimer’s disease (AD). Accumulating evidence suggests that tau pathology co-localizes with RNA binding proteins (RBPs) that are known markers for stress granules (SGs). Here we used proteomics to determine how the network of tau binding proteins changes with disease in the rTg4510 mouse, and then followed up with immunohistochemistry to identify RNA binding proteins that co-localize with tau pathology. The tau interactome networks revealed striking disease-related changes in interactions between tau and a multiple RBPs, and biochemical fractionation studies demonstrated that many of these proteins including hnRNPA0, EWSR1, PABP and RPL7 form insoluble aggregates as tau pathology develops. Immunohistochemical analysis of mouse and human brain tissues suggest a model of evolving pathological interaction, in which RBPs co-localize with pathological phospho-tau but occur adjacent to larger pathological tau inclusions. We suggest a model in which tau initially interacts with RBPs in small complexes, but evolves into isolated aggregated inclusions as tau pathology matures.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0574-5) contains supplementary material, which is available to authorized users.

Fibril formation rewires interactome of the Alzheimer protein Tau by π-stacking

“…We turned the table, using non-physiological aggregates to show that their interactions are based on the same chemical principles driving phase separation. Our paradigm explains recent phenomenological data, showing co-influence of aggregation dynamics between Tau and phaseseparating proteins (Maziuk et al, 2018;Vanderweyde et al, 2016).…”

Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer’s Disease Brain

“…Scale bars: 10 m. RBPs such as TDP-43 form aggregates in AD patient neurons and quite often such granular pTDP-43 aggregates co-localize with GVBs [29,81]. Finally, RBPs associated with SGs progressively accumulate together with tau in neurons of tauopathy mice as well as in human AD and FTLD-tau brain tissue [49]. Thus, it appears reasonable to speculate that not only pTau, but also RBPs could trigger GVD.…”

“…RBPs such as TDP-43 form aggregates in AD patient neurons and quite often granular pTDP-43 aggregates co-localize with GVBs in AD patient hippocampal neurons [29]. Furthermore, RBPs associated with SGs progressively accumulate together with tau in mouse models of tauopathy, as well as in human AD and FTLD-Tau brain tissue [49]. Therefore, in an attempt to identify the trigger for GVD, we next examined RBPs in subicular neu-rons affected by GVD.…”

Dysfunctional RNA‐binding protein biology and neurodegeneration in experimental autoimmune encephalomyelitis in female mice

“…Dysfunctional RBPs, including hnRNP A1 and TAR-DNA binding protein , have been shown to contribute to neurological diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTLD), Alzheimer's disease (AD), and most recently, MS (Ash, Vanderweyde, Youmans, Apicco, & Wolozin, 2014;Deng, Gao, & Jankovic, 2014;Kabashi et al, 2008;Kim et al, 2013;Lagier-Tourenne, Polymenidou, & Cleveland, 2010;Maziuk et al, 2018;Salapa, Johnson, Hutchinson, Popescu, & Levin, 2018;Salapa, Lee, Shin, & Levin, 2017;Vanderweyde et al, 2012). Dysfunctional RBPs, including hnRNP A1 and TAR-DNA binding protein , have been shown to contribute to neurological diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTLD), Alzheimer's disease (AD), and most recently, MS (Ash, Vanderweyde, Youmans, Apicco, & Wolozin, 2014;Deng, Gao, & Jankovic, 2014;Kabashi et al, 2008;Kim et al, 2013;Lagier-Tourenne, Polymenidou, & Cleveland, 2010;Maziuk et al, 2018;Salapa, Johnson, Hutchinson, Popescu, & Levin, 2018;Salapa, Lee, Shin, & Levin, 2017;Vanderweyde et al, 2012).…”

“…RBPs function to maintain RNA homeostasis and play a role in numerous cellular processes, including mRNA stability, function, and transport. Dysfunctional RBPs, including hnRNP A1 and TAR-DNA binding protein (TDP-43), have been shown to contribute to neurological diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTLD), Alzheimer's disease (AD), and most recently, MS (Ash, Vanderweyde, Youmans, Apicco, & Wolozin, 2014;Deng, Gao, & Jankovic, 2014;Kabashi et al, 2008;Kim et al, 2013;Lagier-Tourenne, Polymenidou, & Cleveland, 2010;Maziuk et al, 2018;Salapa, Johnson, Hutchinson, Popescu, & Levin, 2018;Salapa, Lee, Shin, & Levin, 2017;Vanderweyde et al, 2012). Common features of these disorders include a triad of cellular consequences including (a) the formation of persistent stress granules (SGs) in the cytoplasm of cells, (b) mislocalization of the RBP from its normal nuclear location to the cytoplasm, and (c) alterations in RNA metabolism (Polymenidou et al, 2011;Ramaswami, Taylor, & Parker, 2013).…”