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Jiang L, Lin W, Zhang C, Ash PE, Verma M, Kwan J, van Vliet E, Yang Z, Cruz AL, Boudeau S, Maziuk BF, Lei S, Song J, Alvarez VE, Hovde S, Abisambra JF, Kuo MH, Kanaan N, Murray ME, Crary JF, Zhao J, Cheng JX, Petrucelli L, Li H, Emili A, Wolozin B. Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy. Mol Cell. 2021 Oct 21;81(20):4209-4227.e12. Epub 2021 Aug 27 PubMed.
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University of New Mexico
This is an elegant study, which showed a novel mechanism of oligomeric tau causing neurotoxicity through inhibiting protein synthesis in neurons.
The authors optogenetically induced the expression of 4R1N wild-type (WT) tau in lentivirus-transduced primary cortical neurons in a time-dependent manner, which induced tau oligomerization and tau hyperphosphorylation at the T181 and S262 sites. Through proteomic profiling, the authors found that oTau can bind to HNRNPA2B1, a reader of m6A-modified transcripts, and can subsequently induce its nucleus-to-cytoplasm translocation.
HNRNPA2B1 linked oTau with m6A-modified mRNA in the cytoplasm. The oTau/m6A/HNRNPA2B1, which is increased five-fold in the individuals with AD, can further promote stress granule formation and nuclear envelop disruption, reduce protein synthesis, and induce apoptosis. Knocking down HNRNPA2B1 in vitro and in vivo both reduced oTau-induced neurodegeneration.
It will be important to see if knocking down HNRNPA2B1 in older P301S mice can rescue cognitive deficits without any side effects. It will be also important to see if tau oligomers made of 3R-tau have similar neurotoxic effects, which would be applicable to other tauopathies.
Additionally, it will be interesting to see if the oligomeric tau secreted from neurons and taken up by microglial cells exhibit the same neurotoxicity effect through interacting with m6A and HNRNPA2B1 and inhibiting protein synthesis in microglial cells.
View all comments by Shanya JiangUniversity of Texas Medical Branch
The pathological “triade” composed of tau, RNA-binding proteins (RBPs) and RNA molecules strikes again. In recent years, laboratories around the world have published numerous studies on synergistic pathological function of RBPs and RNA in several neurodegenerative diseases. In neurons, toxic tau species, such as oligomers, catalyze the interactions with RBPs in several cell organelles and cellular locations.
In this well-designed study, the Wolozin lab added a new, exciting piece to the puzzle. Their combination of optogenetics (light-reactive bacterial cytochrome 2 – Cry2) and deep proteomic analysis identified HNRNPA2B1 as a principal RBP target of tau oligomer toxicity in stress granules. Moreover, they also observed that this hnRNP works as a molecular linker between tau oligomers and N6-methyladenosine (m6A) modified RNA transcripts. This reinforces growing evidence of synergy between tau and RBPs complexes, suggesting they mediate the progression of tauopathy.
Microtubule-associated protein tau stabilizes microtubules in healthy neurons. However, its aggregation state compromises its physiological functions. In Alzheimer’s disease and other tauopathies, tau hyperphosphorylation and accumulation induce neurotoxic effects at the cellular level, inducing biochemical and structural alterations. However, a knowledge gap in the biological functions of tau inducing stress and disease states still exists.
In this study, optically induced tau-Cry2 oligomers offered the ability to selectively induce tau oligomerization in a temporally controlled manner. This protein-protein interaction approach demonstrated a temporal evolution in tau interaction with different RBPs. The authors observed a perturbation of nuclear envelope components, confirming previous observations that support general RNA transport and metabolism impairment and defects.
Perhaps most importantly, this research points to involvement of m6A RNA transcripts in tauopathies and AD, representing a major finding in the field. The function of m6A is mainly studied in the cancer field, and is minimally investigated in neurodegeneration. This study is the first to link m6A to tau pathology, finding that m6A was transported to the cytoplasm under stress conditions and accumulated with tau oligomers upon tau aggregation induction.
Questions that remain to be addressed include the relative importance of tau oligomerization and phosphorylation, also how oligomerization of tau induces an nucleus-cytoplasm shuttling imbalance of RBPs and m6A transcripts. All these aspects are vital to uncovering the molecular mechanisms of RNA and protein nucleus/cytoplasm transport deficiency in AD and other tauopathies.
In summary, this elegant study demonstrates how tau oligomers function in stress conditions, presenting a new potential mechanism of neurotoxicity that may be suitable for developing new therapeutic strategies.
View all comments by Mauro MontalbanoMake a Comment
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