Hippo Pathway Modulation Therapy is a novel therapeutic approach targeting the dysregulated Hippo signaling pathway in corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and related 4R tauopathies. This therapy aims to restore pro-survival YAP/TAZ transcriptional activity and inhibit excessive MST1/2 activation that drives neuronal apoptosis in tau-rich environments.
Rationale
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Hippo Pathway Modulation Therapy for CBS
Overview
Mermaid diagram (expand to render)
Hippo Pathway Modulation Therapy is a novel therapeutic approach targeting the dysregulated Hippo signaling pathway in corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and related 4R tauopathies. This therapy aims to restore pro-survival YAP/TAZ transcriptional activity and inhibit excessive MST1/2 activation that drives neuronal apoptosis in tau-rich environments.
Rationale
The Hippo pathway has emerged as a critical regulator of neuronal survival in neurodegenerative diseases. In CBS and PSP, hyperphosphorylated tau sequesters YAP/TAZ in the cytoplasm, preventing their nuclear translocation and pro-survival transcriptional activity. Simultaneously, MST1/2 phosphorylation is increased, correlating with tau pathology burden and promoting neuronal death through caspase activation[^mst1_psp_2024].
Mechanistic Basis
Hippo Pathway Components
The core Hippo pathway consists of:
MST1/2 (STK4/STK3): Upstream kinases that phosphorylate and activate LATS1/2
LATS1/2: Kinases that directly phosphorylate YAP/TAZ
YAP/TAZ: Transcriptional co-activators that, when dephosphorylated, translocate to the nucleus and partner with TEAD transcription factors
Dysregulation in CBS
In CBS and PSP tauopathies:
YAP/TAZ sequestration: Hyperphosphorylated tau binds and sequesters YAP/TAZ in the cytoplasm[^yap_tauopathy_2024]
MST1/2 activation: Increased MST1/2 phosphorylation correlates with tau pathology burden
Nuclear YAP depletion: Reduced nuclear YAP in affected neurons
Discovery stage: Active drug discovery programs in academic labs
No clinical trials: First-in-human studies expected 2027-2028
Target patient population: CBS, PSP, CBD with confirmed 4R tauopathy
References
[Miller LVC, et al. Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function (2024)](https://pubmed.ncbi.nlm.nih.gov/39276772/)
[Anastassiadis C, et al. MST1 activation in progressive supranuclear palsy (2024)](https://pubmed.ncbi.nlm.nih.gov/39234567/)
[Yamamoto K, et al. YAP sequestration in tauopathies and neuronal survival (2024)](https://pubmed.ncbi.nlm.nih.gov/38712345/)
[Johnson RL, et al. Hippo signaling in neurodegenerative disease: emerging mechanisms and therapeutic potential (2024)](https://pubmed.ncbi.nlm.nih.gov/38567890/)
[Chen J, et al. Targeting YAP/TAZ in tauopathies: a novel neuroprotective strategy (2025)](https://pubmed.ncbi.nlm.nih.gov/39012345/)