PKR (Protein Kinase R, also known as EIF2AK2) is a serine/threonine protein kinase that plays a central role in the cellular stress response, particularly in antiviral defense and translational control[@b愛德华茲2020]. Also known as double-stranded RNA-dependent protein kinase (DSRNA-PK), PKR is activated by various stress signals including viral RNA, cellular stress, and protein aggregates found in neurodegenerative diseases.
In the context of neurodegenerative disorders, PKR has emerged as a key player in the pathogenesis of Alzheimer's disease, Parkinson's disease, and other conditions. The kinase phosphorylates the translation initiation factor eIF2α, leading to global protein synthesis inhibition, and is activated by various pathological protein aggregates. Understanding PKR's role may lead to therapeutic strategies for neuroprotection.
| Property |
Value |
| Gene |
EIF2AK2 |
| UniProt |
P19589 |
| PDB Structures |
2E7O, 3UI8, 5Y36 |
| Molecular Weight |
~62 kDa |
| Subcellular Localization |
Cytoplasm, nucleus |
| Protein Family |
Serine/Threonine Kinase (PKR family) |
| Expression |
Ubiquitous, high in brain |
PKR contains an N-terminal regulatory domain and a C-terminal kinase domain:
¶ N-terminal Regulatory Domain
- Double-stranded RNA binding domain (DRBD): Binds dsRNA of viral origin
- Zinc finger domain: Involved in protein-protein interactions
- Regulatory motifs: Control kinase activation
¶ C-terminal Kinase Domain
- Kinase subdomain XI: Contains the catalytic site
- Activation loop: Phosphorylation site (Thr446)
- ATP-binding pocket: Target of small molecule inhibitors
- Autophosphorylation: Required for kinase activation
- Dimerization: Induced by dsRNA binding
- Inhibitory proteins: PACT (protein activator of PKR)
PKR is a key component of the innate immune response:
- Binds to double-stranded RNA (viral replication intermediate)
- Activation triggers interferon-stimulated genes
- Blocks viral protein synthesis
- Phosphorylates translation initiation factor eIF2α
- Inhibits global protein synthesis
- Reduces viral replication
- Conserves cellular resources during stress
PKR is part of the integrated stress response (ISR):
- eIF2α phosphorylation is the hallmark of ISR activation
- Four kinases: PKR, PERK, GCN2, HRI
- Common downstream: ATF4-mediated transcription
PKR regulates protein synthesis:
- Global inhibition: Through eIF2α phosphorylation
- Selective translation: Some mRNAs escape inhibition
- Stress granule formation: mRNA sequestration
PKR is implicated in AD through multiple mechanisms:
- PKR is activated in AD hippocampus and frontal cortex
- Activation correlates with disease severity
- Early activation before significant pathology
- Elevated eIF2α-P in AD brains
- Leads to synaptic protein synthesis inhibition
- Contributes to memory impairment
¶ Links to Aβ and Tau
- Amyloid-beta can activate PKR
- Tau pathology enhances PKR activation
- Creates a feed-forward loop of neurodegeneration
PKR links ER stress to neuronal death:
PKR is activated in PD and contributes to dopaminergic neuron death:
- Alpha-synuclein aggregates can activate PKR
- Activated PKR in PD substantia nigra
- Contributes to protein synthesis deficits
- Mitochondrial toxins activate PKR
- Links mitochondrial dysfunction to translational repression
- Exacerbates energy deficits in dopaminergic neurons
- PKR activation in motor neurons
- Contributes to translational inhibition
- Mouse models show protection with PKR deletion
- Mutant huntingtin activates PKR
- Contributes to translational dysfunction
- Therapeutic target
- PKR in demyelination and neuroinflammation
- Contributes to oligodendrocyte death
Several approaches are being developed:
- 2-aminopurine: First-generation inhibitor
- C16: More potent and specific
- Imidazoles: Novel inhibitors in development
- CNS penetration: Essential for neurodegenerative applications
- Selectivity: Avoiding off-target effects
- Timing: When to intervene in disease course
- Targeting upstream activators
- Preventing protein aggregate formation
- Modulating stress responses
- Other ISR kinases can compensate
- eIF2α phosphatases as targets
- ATF4 modulators
- Reducing PKR expression
- Dominant-negative constructs
- Antisense oligonucleotides
- Edwards HG, et al, PKR in neurodegeneration (2020)
- Carroll EC, et al, PKR and Alzheimer's disease (2018)
- Sukhova K, et al, PKR activation in Parkinson's disease (2020)
- Sadigh-Eteghad S, et al, PKR and protein synthesis inhibition (2017)
- Yoshino Y, et al, PKR inhibitors as therapeutic agents in neurodegenerative disease (2019)
- Gomez ML, et al, PKR in viral infections and neurodegeneration (2018)
- Abe T, et al, PKR and translational control in neurons (2018)
- Pezzuto P, et al, PKR knockout protects against neurodegeneration (2019)
- Ong ML, et al, PKR activation and the integrated stress response (2017)
- Duttagupta P, et al, PKR in neuroinflammation (2019)