[^1]
[^2]
[^3]
[^4]
[^5]
[^6]
| Symbol | YAP1 |
| Full Name | Yes-Associated Protein 1 |
| Chromosome |
11q22.1 |
| NCBI Gene |
10413 |
| Ensembl |
ENSG00000137693 |
| OMIM |
606608 |
| UniProt |
P46937 |
| Protein |
[YAP1 Protein](/proteins/yap1-protein) |
| Diseases |
[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), [Huntington's Disease](/diseases/huntingtons), [ALS](/diseases/als) |
| Expression |
[Hippocampus](/brain-regions/hippocampus), [Cortex](/brain-regions/cortex), Cerebellum, Substantia nigra (widespread) |
| Hippo signaling, Wnt/β-catenin, TGF-β, Notch crosstalk, mechanotransduction |
YAP1 (Yes-Associated Protein 1) is a transcriptional coactivator and the primary downstream effector of the Hippo signaling pathway, located on chromosome 11q22.1. YAP1 acts as an oncogene in many cancers but has emerged as a critical regulator of neuronal survival, neuroinflammation, and neurodegeneration. When the Hippo pathway is inactive, YAP1 translocates to the nucleus where it binds TEAD transcription factors to drive expression of genes involved in cell survival, proliferation, and anti-apoptotic programs. When Hippo signaling is active, LATS1/LATS2 kinases phosphorylate YAP1 at serine 127, leading to cytoplasmic retention by 14-3-3 proteins and subsequent proteasomal degradation.
In the central nervous system, YAP1 plays essential roles in neural progenitor proliferation, neuronal differentiation, astrocyte reactivity, and microglial activation. Dysregulation of YAP1 signaling has been implicated in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and traumatic brain injury.
The YAP1 gene spans approximately 122 kb of genomic DNA on chromosome 11q22.1 and consists of 9 exons. Alternative splicing produces multiple isoforms, with YAP1-1 (containing one WW domain) and YAP1-2 (containing two WW domains) being the most functionally characterized. The two-WW-domain isoform shows preferential interaction with LATS1/LATS2 and distinct transcriptional target specificity.
- TEAD-responsive elements: YAP1 expression is partially auto-regulated through TEAD-dependent transcription
- NF-κB response elements: Inflammatory signaling upregulates YAP1 in glial cells
- Hippo pathway feedback: MST1/MST2 and LATS1/2 regulate YAP1 post-translationally
- Mechanosensitive regulation: ECM stiffness and cell geometry control YAP1 nuclear localization
YAP1 serves multiple critical roles in the nervous system:
-
Neural development: YAP1 is essential for neural progenitor cell proliferation and maintenance of the neural stem cell pool during cortical development. Conditional knockout of YAP1 in neural progenitors causes premature differentiation and microcephaly.
-
Neuronal survival: In mature neurons, YAP1 promotes expression of anti-apoptotic genes including BCL2L1 (Bcl-xL), BIRC5 (Survivin), and CTGF. Nuclear YAP1 activity is required to suppress neuronal death following excitotoxic stress.
-
Synaptic function: YAP1 regulates expression of synaptic adhesion molecules and scaffolding proteins. It modulates dendritic spine density and synaptic transmission through TEAD-dependent transcription of DLG4 (PSD-95) family members.
-
Astrocyte reactivity: YAP1 is highly expressed in reactive astrocytes and drives the A2 neuroprotective phenotype. YAP1 activation in astrocytes promotes BDNF and GDNF secretion.
-
Microglial polarization: YAP1 regulates microglial inflammatory responses, with nuclear YAP1 generally promoting anti-inflammatory M2-like polarization via suppression of NF-κB target genes.
The canonical Hippo pathway cascade controlling YAP1:
graph TD
A["MST1/MST2 kinases"] -->|"Phosphorylate"| B["LATS1/LATS2 kinases"]
B -->|"Phosphorylate S127"| C["YAP1 (cytoplasmic)"]
C -->|"14-3-3 binding"| D["Cytoplasmic retention"]
D -->|"Ubiquitination"| E["Proteasomal degradation"]
F["Hippo OFF / Mechanical signals"] -->|"Inhibit"| A
F -->|"Enable"| G["YAP1 (nuclear)"]
G -->|"Binds TEAD1-4"| H["Target gene transcription"]
H --> I["CTGF, CYR61, BIRC5, BCL2L1"]
H --> J["Cell survival & proliferation"]
YAP1 dysfunction is increasingly recognized as a contributor to Alzheimer's disease pathogenesis:
- Amyloid-β toxicity: Aβ oligomers activate MST1 kinase, leading to YAP1 phosphorylation and cytoplasmic sequestration. Loss of nuclear YAP1 removes the neuroprotective transcriptional program, sensitizing neurons to apoptosis.
- Tau pathology: Hyperphosphorylated tau disrupts YAP1 nuclear localization by interfering with nuclear transport machinery. YAP1 levels are reduced in neurofibrillary tangle-bearing neurons.
- Reduced YAP1 in AD brains: Post-mortem studies show decreased nuclear YAP1 in hippocampal and cortical neurons of AD patients compared to age-matched controls, correlating with Braak staging.
- TEAD target suppression: Downstream YAP1-TEAD targets including survival factors are downregulated in AD, contributing to neuronal vulnerability.
- Dopaminergic neuron vulnerability: YAP1 is expressed in substantia nigra dopaminergic neurons. Oxidative stress from dopamine metabolism activates MST1, phosphorylating YAP1 and reducing its nuclear activity.
- LRRK2 interaction: LRRK2 G2019S gain-of-function mutation enhances MST1/LATS2 activity, promoting excessive YAP1 phosphorylation. This provides a mechanistic link between LRRK2 mutations and dopaminergic neuron death.
- α-Synuclein effects: α-Synuclein aggregates activate the Hippo pathway through mechanical stress sensing, driving YAP1 cytoplasmic retention and loss of neuroprotective gene expression.
- Mitophagy connection: YAP1 regulates expression of mitophagy genes and interacts with PINK1/Parkin pathway components, linking Hippo signaling to mitochondrial quality control.
- Mutant huntingtin: Expanded polyglutamine tracts in HTT directly interact with YAP1's WW domains, sequestering YAP1 in cytoplasmic aggregates and preventing its nuclear function.
- Striatal vulnerability: Medium spiny neurons of the striatum show particularly high dependence on YAP1-TEAD survival signaling, potentially explaining their selective vulnerability in HD.
- Transcriptional dysregulation: Loss of nuclear YAP1 contributes to the widespread transcriptional dysregulation characteristic of HD, particularly affecting neuronal survival and synaptic genes.
- Motor neuron survival: YAP1 is expressed in spinal motor neurons and promotes survival through TEAD-dependent transcription of BCL2 family anti-apoptotic factors.
- SOD1 mutations: Mutant SOD1 activates MST1 kinase in motor neurons, driving YAP1 phosphorylation and nuclear exclusion before the onset of motor symptoms.
- Glial YAP1: Reactive astrocytes in ALS show increased nuclear YAP1, which may represent a compensatory neuroprotective response but can become maladaptive in chronic disease.
YAP1 is broadly expressed throughout the nervous system with regional and cell-type-specific differences:
- Hippocampus: High expression in CA1 and CA3 pyramidal neurons; moderate in dentate gyrus granule cells
- Cortex: Expressed in pyramidal neurons across all layers; enriched in layer V
- Cerebellum: Purkinje cells and Bergmann glia show robust expression
- Substantia nigra: Moderate expression in dopaminergic neurons; higher in glial cells
- Astrocytes: Expression increases dramatically upon reactive astrogliosis
- Microglia: Low baseline expression; upregulated upon activation
- Oligodendrocyte precursors: Required for OPC proliferation and myelination
During development, YAP1 expression is highest in neural progenitor zones (ventricular and subventricular zones) and decreases as neurons terminally differentiate, though mature neurons retain functional YAP1 expression.
Given that loss of nuclear YAP1 contributes to neuronal death across multiple neurodegenerative diseases, therapeutic activation of YAP1 is being explored:
- MST1/2 inhibitors: Small molecules inhibiting MST1/2 kinases prevent YAP1 phosphorylation and maintain nuclear YAP1 activity. XMU-MP-1 has shown neuroprotective effects in preclinical AD and PD models.
- LATS1/2 inhibitors: Targeting LATS kinases directly prevents YAP1 S127 phosphorylation.
- Verteporfin considerations: While verteporfin disrupts YAP1-TEAD interaction (used in cancer), its use in neurodegeneration would be counterproductive.
- Statins: Some statins activate YAP1 by modulating the mevalonate pathway, which regulates Rho GTPase-dependent YAP1 nuclear localization.
- AAV-mediated delivery of constitutively active YAP1 (S127A mutant) has shown neuroprotection in mouse models of neurodegeneration
- CRISPR activation of endogenous YAP1 is being explored as a more controlled approach