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Research highlights: Targeted Protein Degradation in Tauopathies

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By Ncardia Stem Cell Experts

iPSC-derived neuron models of tauopathy assist in the identification of targeted degraders

Tauopathies are neurodegenerative diseases characterized by the aberrant accumulation of misfolded tau protein in the brain. Some well-known tauopathies are Alzheimer’s disease (AD) and frontotemporal dementia (FTD). There are no effective therapies available, despite their increasing prevalence among a globally aging population.

Targeted protein degraders are a novel type of therapeutic drugs –the first of its kind was approved for clinical use in 2019 [1] – with potential for treating diseases characterized by the accumulation of misfolded proteins, such as tauopathies. This is because, as their name indicates, they can be directed against misfolded or aberrant proteins, labeling them for degradation by the cell's proteasome. 

Targeted protein degradation programs frequently use heterologous model systems with recombinant protein overexpression and/or simplified cellular systems that do not accurately replicate important aspects of disease biology. However, to develop efficient tau degraders, using patient-relevant models is key as they recapitulate neuronal endogenous, non-heterologous tau expression under genomic and physiological contexts.

This explains why Silva et al. used induced pluripotent stem cells (iPSC)-derived neurons from FTD patients as primary models for identifying tau targeting degrader proteins, which naturally expressed a tau mutation [2]. What’s more, patient-specific iPSC-derived neurons have tau phenotypes that are genotype dependent and disease relevant, which is unachievable with other models. In addition, early alterations in brain development and homeostasis contribute to later manifestations of neurodegenerative diseases. This highlights the benefits of using iPSC-derived systems to study such diseases.

The research group specialized in development of protein degraders, used iPSCs to test structure-activity (SAR) relationships of compounds with potential to reduce tau levels in a disease-relevant context. They identified a lead compound, called QC-01-175. This compound was further optimized to achieve an increased tau reduction in FTD neuron models, as well as degradation of insoluble tau and a prolonged effect on tau levels. This last result particularly supports the therapeutic potential of tau degraders.

This assumption would not have been possible if the research was conducted in cellular systems where tau heterologous overexpression and aggregation deviate from physiological conditions. This shows another advantage of using patient-derived iPSC models for degrader identification and characterization. 

Key points

  • Protein degraders are new drugs which can specifically label misfolded or aberrant disease-causing proteins for degradation.

  • The optimal development and testing of protein degraders requires cellular models that recapitulate endogenous protein expression.

  • Patient-specific iPSC-derived neurons meet this important requirement, thus facilitate the discovery and optimization of targeted protein degraders.


[1] Mullard, A. First targeted protein degrader hits the clinic. Nat Rev Drug Discov. 2019 Mar 6. doi: 10.1038/d41573-019-00043-6. Accessed March 13, 2023.

[2] Silva MC, et al. Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy. Front Cell Neurosci. 2022 Mar 3;16:801179. doi: 10.3389/fncel.2022.801179.