Targeted tau protein degradation: a promising therapeutic approach for tauopathies

Dec 5, 2025Neuroscience

Breaking Down Tau Protein as a Possible Treatment for Tau-Related Brain Diseases

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Tauopathies are associated with the pathological aggregation of tau proteins, which have proven resilient to conventional drug treatment.

Traditional therapeutic strategies for tauopathies have failed in clinical trials.
Conventional drugs struggle to target disease-causing tau proteins due to their lack of a stable structure.
Tau's flexible conformation makes it a suitable target for targeted protein degradation (TPD) approaches.
TPD utilizes bifunctional molecules to recruit tau to cellular degradation systems, potentially improving treatment outcomes.
Current advancements in TPD strategies may offer advantages over traditional small-molecule inhibitors for tauopathies.

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Tauopathies are a spectrum of diseases characterized by the pathological aggregation of tau proteins. Several therapeutic strategies have been developed to treat or stop the progression of these diseases, but all have failed in clinical trials. One potential reason for these failures is that disease-causing proteins are resilient to treatment with conventional drugs since they lack a predefined monomeric structure and an active binding site. Tau is an intrinsically disordered protein; paradoxically, its flexible conformation makes it an ideal candidate for targeted protein degradation (TPD) approaches, which bypass the need for structured binding pockets by inducing proximity-based recruitment to degradative machinery. TPD uses bifunctional molecules to recruit proteins to the ubiquitin-proteasome system (UPS) or autophagy-lysosomal pathways, overcoming limitations of traditional small-molecule inhibitors (SMIs). As these technologies have been effective in degrading several disease-related proteins, they hold significant promise for treating tauopathies caused by protein aggregation. Herein, we review the tau structure and functions, summarize the main post-translational modifications (PTMs) of tau including those causing pathological aggregation of tau, the major degradative cellular machinery and their defects in pathological state, and discuss the advantages and current progress of targeted protein degradation strategies compared to traditional approaches.

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Targeted tau protein degradation: a promising therapeutic approach for tauopathies

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