ER stress, UPR pathways (PERK, IRE1, ATF6), calcium dysregulation, protein misfolding, and therapeutic targeting in PSP
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) represent critical cellular stress pathways in Progressive Supranuclear Palsy (PSP). The ER is essential for protein folding, calcium homeostasis, and lipid biosynthesis. When these functions are disrupted, the UPR is activated to restore cellular homeostasis. In PSP, chronic ER stress contributes to neuronal dysfunction and tau pathology progression.
ER stress is prominently activated in PSP brain tissue[1][2]:
| Region | ER Stress Markers | Severity |
|---|---|---|
| Globus pallidus | CHOP, BiP upregulation | High |
| Substantia nigra | eIF2α phosphorylation | High |
| Frontal cortex | XBP1 splicing | Moderate |
| Brainstem nuclei | ATF4 expression | Moderate |
Multiple mechanisms contribute to ER stress in PSP:
The UPR is mediated by three ER transmembrane sensors[3]:
The PERK (PKR-like ER kinase) pathway is prominently activated in PSP[4]:
| PERK Component | PSP Finding | Functional Impact |
|---|---|---|
| p-eIF2α | 2-3 fold increase | Translation suppression |
| ATF4 | Elevated | Pro-apoptotic genes |
| CHOP | Strong upregulation | Cell death pathway |
The IRE1 (Inositol-requiring enzyme 1) pathway shows dysregulation in PSP:
XBP1 Splicing:
IRE1 RNase Activity:
ATF6 (Activating transcription factor 6) activation in PSP:
ER calcium handling is disrupted in PSP[5]:
| Calcium Channel | PSP Status | Effect |
|---|---|---|
| SERCA pumps | Reduced | Impaired ER Ca²⁺ uptake |
| IP3 receptors | Dysregulated | Altered Ca²⁺ release |
| RyR channels | Altered | Calcium leak |
| Store-operated channels | Impaired | Reduced refill |
ER-mitochondria contact sites (MAMs) are altered in PSP[6]:
| MAM Function | PSP Status | Contribution |
|---|---|---|
| Calcium signaling | Dysregulated | Apoptosis |
| Lipid synthesis | Altered | Membrane dysfunction |
| Autophagy regulation | Impaired | Protein clearance |
| Apoptosis initiation | Enhanced | Neuronal loss |
Tau pathology directly induces ER stress[7][8]:
The UPR modulates tau pathology:
| UPR Pathway | Effect on Tau | Mechanism |
|---|---|---|
| PERK | Increased phosphorylation | eIF2α → GSK3β activation |
| IRE1 | Variable | JNK-mediated effects |
| ATF6 | May reduce aggregation | Chaperone upregulation |
ER stress triggers autophagy as a protective response[9]:
ER stress markers in PSP:
| Marker | Sample | Potential Use |
|---|---|---|
| BiP/GRP78 | CSF | Diagnostic |
| CHOP | Blood | Disease progression |
| XBP1 splicing | Blood | Therapeutic target |
| p-eIF2α | CSF | Prognosis |
ER stress modulators under investigation[10]:
| Target | Approach | Status |
|---|---|---|
| PERK inhibitors | Small molecules | Preclinical |
| IRE1 RNase modulators | Natural compounds | Research |
| Chaperone inducers | Chemical chaperones | Early research |
| Calcium stabilizers | SERCA modulators | Research |
| Feature | PSP | CBD | CBD Overlap |
|---|---|---|---|
| CHOP elevation | High | High | High |
| XBP1 splicing | Moderate | High | Moderate |
| ATF6 activation | Moderate | Moderate | Moderate |
| ER-calcium dysregulation | Prominent | Prominent | Present |
ER stress and UPR activation are prominent features of PSP pathogenesis. The chronic activation of all three UPR pathways (PERK, IRE1, ATF6) contributes to neuronal dysfunction through:
Key Takeaways:
ER stress in 4R tauopathies. Acta Neuropathol Commun. 2018. ↩︎
Endoplasmic reticulum stress in neurodegenerative diseases. J Neurol Sci. 2020. ↩︎
The unfolded protein response: from stress signaling to cell fate decisions. Cell. 2005. ↩︎
ER stress and Alzheimer's disease: the unfolded protein response and translational control. Ageing Res Rev. 2020. ↩︎
Calcium dysregulation and endoplasmic reticulum stress in neurodegenerative diseases. J Cell Physiol. 2022. ↩︎
The role of endoplasmic reticulum-mitochondria contact sites in cellular health and disease. Front Cell Dev Biol. 2020. ↩︎
ER stress and tauopathy. J Alzheimers Dis. 2018. ↩︎
Tau induces ER stress through activation of PERK and IRE1. J Alzheimers Dis. 2018. ↩︎
ER stress and autophagy in neurodegenerative diseases. Autophagy. 2014. ↩︎
Targeting the unfolded protein response for disease modification. Pharmacol Ther. 2020. ↩︎