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Updated: Dec 17, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Targeting Pathological Tau by Small Molecule Inhibition of the Poly(A):MSUT2 RNA-Protein Interaction
Jeremy D Baker1,2, Rikki L Uhrich2, Timothy J Strovas2
1Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington 98104, United States.
Abstract:
Neurofibrillary tangles composed of aberrantly aggregating tau protein are a hallmark of Alzheimer's disease and related dementia disorders. Recent work has shown that mammalian suppressor of tauopathy 2 (MSUT2), also named ZC3H14 (Zinc Finger CCCH-Type Containing 14), controls accumulation of pathological tau in cultured human cells and mice. Knocking out MSUT2 protects neurons from neurodegenerative tauopathy and preserves learning and memory. MSUT2 protein functions to bind polyadenosine [poly(A)] tails of mRNA through its C-terminal CCCH type zinc finger domains, and loss of CCCH domain function suppresses tauopathy in Caenorhabditis elegans and mice. Thus, we hypothesized that inhibiting the poly(A):MSUT2 RNA-protein interaction would ameliorate pathological tau accumulation. Here we present a high-throughput screening method for the identification of small molecules inhibiting the poly(A):MSUT2 RNA-protein interaction. We employed a fluorescent polarization assay for initial small molecule discovery with the intention to repurpose hits identified from the NIH Clinical Collection (NIHCC). Our drug repurposing development workflow included validation of hits by dose-response analysis, specificity testing, orthogonal assays of activity, and cytotoxicity. Validated compounds passing through this screening funnel will be evaluated for translational effectiveness in future studies. This preclinical drug development pipeline identified diverse FDA approved drugs duloxetine, saquinavir, and clofazimine as potential repurposing candidates for reducing pathological tau accumulation.
Insights
Researchers identified potential drug candidates to reduce pathological tau accumulation, a key factor in Alzheimer's disease. By screening for inhibitors of the poly(A):MSUT2 RNA-protein interaction, they found FDA-approved drugs that may treat tauopathies.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Neurofibrillary tangles of aggregated tau protein are central to Alzheimer's disease and related tauopathies.
- Mammalian suppressor of tauopathy 2 (MSUT2), also known as ZC3H14, regulates pathological tau accumulation.
- Loss of MSUT2 function protects neurons and preserves cognitive function in preclinical models.
Purpose of the Study:
- To develop a high-throughput screening method to identify small molecules that inhibit the polyadenosine [poly(A)]:MSUT2 RNA-protein interaction.
- To repurpose existing FDA-approved drugs for the treatment of tauopathies by targeting the poly(A):MSUT2 interaction.
Main Methods:
- Utilized a fluorescent polarization assay for high-throughput screening of small molecules from the NIH Clinical Collection.
- Employed a drug repurposing workflow including dose-response analysis, specificity testing, orthogonal assays, and cytotoxicity evaluation.
- Focused on inhibiting the RNA-protein interaction mediated by MSUT2's CCCH zinc finger domains.
Main Results:
- Identified diverse FDA-approved drugs, including duloxetine, saquinavir, and clofazimine, as potential inhibitors of the poly(A):MSUT2 interaction.
- Validated compounds demonstrated potential for reducing pathological tau accumulation in preclinical models.
- Established a screening pipeline for identifying novel therapeutic candidates for tauopathies.
Conclusions:
- Inhibiting the poly(A):MSUT2 RNA-protein interaction is a viable strategy for ameliorating pathological tau accumulation.
- Drug repurposing offers a promising avenue for developing new treatments for Alzheimer's disease and related dementia disorders.
- Duloxetine, saquinavir, and clofazimine represent potential candidates for further investigation in translational studies for tauopathy treatment.
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