Hippo Pathway In Neurodegeneration plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
The Hippo signaling pathway is a highly conserved kinase cascade that regulates organ size, cell proliferation, and tissue homeostasis. Originally discovered in Drosophila, this pathway has emerged as a critical regulator of neuronal survival, stem cell function, and neurodegeneration[1].
| Component | Function | Neurodegeneration Relevance |
|---|---|---|
| MST1/2 (Hippo) | Kinase, activates LATS1/2 | Pro-apoptotic in neurons |
| SAV1 | Scaffold protein | Forms complex with MST1/2 |
| LATS1/2 | Kinase, phosphorylates YAP/TAZ | Tumor suppressor |
| MOB1A/B | Scaffold for LATS | Essential for kinase activity |
| YAP/TAZ | Transcriptional co-activators | Pro-survival when active |
| TEAD1-4 | Transcription factors | Partner YAP/TAZ |
The Hippo pathway intersects with Alzheimer's disease through multiple mechanisms:
| Target | Approach | Status |
|---|---|---|
| MST1 inhibitors | Block pro-apoptotic kinase | Preclinical |
| YAP activators | Promote nuclear localization | Investigational |
| TEAD agonists | Enhance pro-survival transcription | Early research |
The Hippo pathway plays a critical role in dopaminergic neuron survival:
ALS shows specific Hippo pathway dysregulation:
The Hippo pathway regulates microglial function:
Hippo pathway modulators may reduce neuroinflammation:
YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) serve as key transcriptional effectors of the Hippo pathway with significant neuroprotective functions[2]:
In neurodegeneration, YAP nuclear localization is compromised:
Strategies to restore YAP/TAZ activity include:
Recent research has revealed a critical connection between Hippo signaling and ferroptosis, a form of iron-dependent cell death[5]:
MST1 (Mammalian STE20-like protein kinase 1) is a central mediator of stress-induced neuronal death[7]:
Activation triggers:
Downstream targets:
LATS1/2 (Large tumor suppressor kinases) phosphorylate YAP/TAZ:
| Partner | Function | Neurodegeneration Relevance |
|---|---|---|
| TEAD1-4 | Pro-survival gene activation | Reduced in AD |
| SMADs | TGF-β signaling | Altered in PD |
| p73 | Apoptosis regulation | Impaired in ALS |
| Runx1 | Differentiation | Dysregulated |
| Compound | Target | Mechanism | Development Stage |
|---|---|---|---|
| Xmu-mp-1 | MST1 | Kinase inhibitor | Preclinical[8] |
| Verteporfin | YAP-TEAD | Interaction inhibitor | Research |
| CBL-0137 | YAP | Nuclear translocation | Preclinical |
| Dexamethasone | MST1 | Kinase modulation | Preclinical |
Several compounds are in various stages of development[9]:
| Agent | Target | Stage | Indication |
|---|---|---|---|
| Xmu-mp-1 | MST1 | Preclinical | AD |
| Verteporfin | YAP-TEAD | Research | PD |
| CBL-0137 | YAP | Preclinical | ALS |
The Hippo pathway intersects with mTOR signaling in neurodegeneration:
YAP/TAZ regulate autophagic genes:
Hippo pathway influences mitochondrial function:
Wang L, et al. A metabolic cell death program downstream of SARM1 couples NAD(+) depletion to BAX activation and APAF1 degradation. Cell. 2024. ↩︎
Hansen M, et al. YAP/TAZ signaling in neuronal stress response and neurodegenerative disease. Nature Reviews Neuroscience. 2021. ↩︎
Zhao L, et al. Hippo pathway dysregulation in Alzheimer's disease brain. Acta Neuropathologica Communications. 2022. ↩︎
Yang C, et al. Hippo pathway in Parkinson's disease: role of alpha-synuclein in regulating YAP nuclear localization. Cell Death & Disease. 2023. ↩︎
Wang J, et al. Ferroptosis and the Hippo pathway: new insights into neurodegeneration. Cellular and Molecular Neurobiology. 2024. ↩︎
Xie Y, et al. Inhibition of Hippo Signaling Through Ablation of Lats1 and Lats2 Protects Against Cognitive Decline in 5xFAD Mice via Increasing Neuronal Resilience Against Ferroptosis. Cell Reports. 2024. ↩︎
Uhl M, et al. Hippo pathway kinases in neurodegeneration: new insights into molecular mechanisms. Cellular and Molecular Life Sciences. 2020. ↩︎
Qin X, et al. Xmu-mp-1 attenuates streptozotocin-induced neurotoxicity in SH-SY5Y cells: potential role of Hippo pathway modulation. Neuropharmacology. 2024. ↩︎
Chiang AC, et al. Modulators of YAP/TAZ activity as neuroprotective agents. Journal of Medicinal Chemistry. 2024. ↩︎