ER Stress and Unfolded Protein Response in Progressive Supranuclear Palsy

ER Stress and Unfolded Protein Response in Progressive Supranuclear Palsy

Introduction

Progressive Supranuclear Palsy (PSP) is a 4-repeat (4R) tauopathy characterized by the accumulation of hyperphosphorylated tau protein in neurons and glia. Like other neurodegenerative diseases, PSP exhibits significant endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). The UPR is a conserved cellular stress response that attempts to restore ER homeostasis by reducing protein translation, increasing chaperone expression, and enhancing protein degradation. However, in PSP, chronic ER stress leads to sustained UPR activation, ultimately resulting in neuronal dysfunction and death through multiple signaling pathways including PERK, IRE1, and ATF6. [@ma2020]

This page provides a comprehensive analysis of ER stress and UPR mechanisms specifically in PSP, comparing them to Alzheimer's disease (AD) and Parkinson's disease (PD), and discussing emerging therapeutic strategies targeting these pathways. [@das2021]

ER Stress in PSP: Overview

ER stress in PSP arises from multiple converging mechanisms:

Tau protein overload: The accumulation of hyperphosphorylated 4R tau places significant burden on the ER protein folding machinery

Calcium dysregulation: PSP neurons exhibit impaired calcium homeostasis, affecting ER function

Oxidative stress: Increased reactive oxygen species (ROS) in PSP brains damage ER proteins

Mitochondrial dysfunction: Energy impairment in PSP affects ER ATP-dependent processes

...

ER Stress and Unfolded Protein Response in Progressive Supranuclear Palsy

Introduction

Progressive Supranuclear Palsy (PSP) is a 4-repeat (4R) tauopathy characterized by the accumulation of hyperphosphorylated tau protein in neurons and glia. Like other neurodegenerative diseases, PSP exhibits significant endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). The UPR is a conserved cellular stress response that attempts to restore ER homeostasis by reducing protein translation, increasing chaperone expression, and enhancing protein degradation. However, in PSP, chronic ER stress leads to sustained UPR activation, ultimately resulting in neuronal dysfunction and death through multiple signaling pathways including PERK, IRE1, and ATF6. [@ma2020]

This page provides a comprehensive analysis of ER stress and UPR mechanisms specifically in PSP, comparing them to Alzheimer's disease (AD) and Parkinson's disease (PD), and discussing emerging therapeutic strategies targeting these pathways. [@das2021]

ER Stress in PSP: Overview

ER stress in PSP arises from multiple converging mechanisms:

Tau protein overload: The accumulation of hyperphosphorylated 4R tau places significant burden on the ER protein folding machinery

Calcium dysregulation: PSP neurons exhibit impaired calcium homeostasis, affecting ER function

Oxidative stress: Increased reactive oxygen species (ROS) in PSP brains damage ER proteins

Mitochondrial dysfunction: Energy impairment in PSP affects ER ATP-dependent processes

The combination of these factors triggers the UPR as a compensatory mechanism, but chronic activation becomes pathological.

The Three UPR Branches in PSP

1. PERK Pathway

The Protein Kinase R (PKR)-like ER kinase (PERK/EIF2AK3) pathway is the most extensively studied UPR branch in PSP.

Mechanism

Under ER stress, PERK oligomerizes and autophosphorylates, then phosphorylates [eukaryotic initiation factor 2α (eIF2α)](https://en.wikipedia.org/wiki/EIF2S1) at Ser51. This phosphorylation:

• Globally suppresses protein translation
• Selectively promotes translation of ATF4, a transcription factor that upregulates genes involved in:
• Amino acid metabolism
• Antioxidant responses
• Apoptosis (including CHOP/DDIT3)

Evidence in PSP

Studies have demonstrated increased PERK activation and eIF2α phosphorylation in PSP brain tissue, particularly in neurons containing tau pathology. The PERK-eIF2α-ATF4-CHOP axis is prominently activated in:

• Substantia nigra pars compacta neurons
• Brainstem nuclei affected in PSP
• Cortical neurons in PSP with cortical involvement

The chronic activation of PERK in PSP leads to prolonged eIF2α phosphorylation, which paradoxically impairs synaptic function and neuronal connectivity while attempting to reduce protein load.

2. IRE1 Pathway

Inositol-requiring enzyme 1 (IRE1/ERN1) has two functional domains:

• A kinase domain that autophosphorylates under ER stress
• An endoribonuclease domain that splices XBP1 mRNA

XBP1 Splicing

Activated IRE1 splices XBP1 mRNA, removing a 26-nucleotide intron to produce XBP1s (spliced form). XBP1s is a transcription factor that:

• Upregulates ER chaperones (BiP/GRP78, GRP94)
• Enhances ER-associated degradation (ERAD) components
• Promotes lipid synthesis for ER expansion

IRE1 RNase Activity

Beyond XBP1 splicing, IRE1's RNase activity can:

• Degrade ER-localized mRNAs (RIDD - IRE1-dependent decay)
• Process microRNAs involved in synaptic function
• Trigger apoptosis when activation is prolonged

In PSP, IRE1 activation contributes to:

• Increased XBP1s expression in affected neurons
• Dysregulated calcium signaling through IP3 receptor interactions
• Potential contribution to tau phosphorylation through downstream effects

3. ATF6 Pathway

Activating transcription factor 6 (ATF6) is a type II transmembrane protein that traffics to the Golgi under ER stress, where it is cleaved by proteases S1P and S2P.

Cleavage and Activation

ATF6 cleavage releases a cytosolic fragment (ATF6f) that translocates to the nucleus and:

• Binds to ER stress response elements (ERSE)
• Upregulates ER chaperones (BiP, XBP1, CHOP)
• Increases components of protein degradation systems

Role in PSP

ATF6 activation in PSP is complex:

• Acute ATF6 activation is protective, increasing chaperone capacity
• Chronic ATF6 activation can contribute to apoptosis through CHOP induction
• Genetic variations in ATF6 may influence PSP susceptibility

Calcium Dysregulation in PSP

Calcium homeostasis is critically impaired in PSP, and this dysfunction both results from and contributes to ER stress.

Mechanisms

ER Calcium Depletion: PSP neurons show reduced ER calcium stores due to:

• Impaired SERCA (sarco/endoplasmic reticulum Ca2+-ATPase) function
• Increased calcium leak through ryanodine receptors
• Altered IP3 receptor signaling

Mitochondrial-Calcium Coupling: The close physical association between ER and mitochondria means calcium dysregulation in one organelle affects the other:

• Excessive calcium release from ER can overload mitochondria
• Mitochondrial dysfunction reduces calcium buffering capacity
• This creates a vicious cycle exacerbating both ER stress and mitochondrial dysfunction

Voltage-Gated Calcium Channel Alterations: PSP brains show changes in calcium channel expression and function, affecting calcium influx and ER refilling

Consequences for UPR

Calcium dysregulation directly impacts UPR signaling:

• Calmodulin-dependent PERK activation
• Calcium-dependent chaperone function impairment
• Activation of calcium-sensitive proteases (calpains) that can cleave UPR components

CHOP-Mediated Apoptosis

[CCAAT/enhancer-binding protein homologous protein (CHOP/DDIT3)](https://en.wikipedia.org/wiki/CHOP), also known as GADD153, is the primary executor of UPR-induced apoptosis.

Regulation

CHOP is induced by all three UPR branches:

• ATF4 (PERK branch)
• XBP1s (IRE1 branch)
• ATF6f (ATF6 branch)

Pro-Apoptotic Mechanisms

CHOP promotes apoptosis through multiple mechanisms:

Transcriptional Repression

• Downregulates anti-apoptotic Bcl-2
• Upregulates pro-apoptotic BIM
• Promotes ERO1α expression, increasing ER oxidative stress

ER Oxidoreductases

• Induces ERO1α, which oxidizes the ER lumen
• Promotes calcium release through IP3 receptors
• Increases ROS generation

Protein Synthesis

• Promotes expression of GADD34, which dephosphorylates eIF2α
• This restores translation but floods the ER with proteins it cannot fold
• Leads to terminal ER stress and apoptosis

Drp1 Translocation

• CHOP can promote mitochondrial fission through Drp1/DNM1L
• This increases mitochondrial vulnerability to apoptosis

CHOP in PSP

CHOP expression is elevated in PSP brain tissue, particularly in:

• Tau-laden neurons in the substantia nigra
• Brainstem nuclei (red nucleus, oculomotor nucleus)
• Affected cortical regions

The presence of CHOP-positive neurons correlates with TUNEL-positive apoptotic cells, suggesting active cell death pathways.

Comparison to Alzheimer's Disease and Parkinson's Disease

Shared Features

All three major neurodegenerative diseases show ER stress and UPR activation:

| Feature | AD | PD | PSP |
|---------|----|----|-----|
| PERK activation | ++ | ++ | +++ |
| IRE1/XBP1 | ++ | ++ | ++ |
| ATF6 | ++ | ++ | ++ |
| CHOP | ++ | ++ | +++ |
| eIF2α-P | ++ | + | +++ |

Disease-Specific Patterns

Alzheimer's Disease:

• Aβ and tau pathology directly induce ER stress
• PERK-eIF2α pathway shows strong activation
• Early UPR involvement in disease progression
• CHOP contributes to synaptic loss

Parkinson's Disease:

• ER stress induced by α-synuclein accumulation
• IRE1 pathway particularly prominent
• PD-linked mutations (LRRK2, PARK2, PINK1) affect ER-mitochondrial contact sites
• Strong link to mitochondrial dysfunction

Progressive Supranuclear Palsy:

• 4R tau overload is primary ER stressor
• PERK-eIF2α-CHOP axis most strongly activated
• Calcium dysregulation is a major contributor
• Greater baseline UPR activation compared to AD/PD
• Brainstem neurons particularly vulnerable

Vulnerability Patterns

The pattern of UPR activation in PSP correlates with its characteristic neuropathology:

• Substantia nigra: High PERK/CHOP → dopaminergic neuron loss
• Brainstem nuclei: Sustained eIF2α phosphorylation → oculomotor dysfunction
• Basal ganglia: Corticostriatal pathway disruption → akinesia/bradykinesia
• Cerebellum: Axonal involvement → gait disorder

Therapeutic Targeting

UPR Modulators

PERK Inhibitors

• GSK2606414: First-generation PERK inhibitor, shows neuroprotection in tauopathy models
• GSK2656157: More specific PERK inhibitor, being explored for neurodegenerative diseases
• Challenge: Systemic toxicity limits translation; brain-penetrant versions needed

IRE1 Modulators

• MKC8866: IRE1 RNase inhibitor, reduces pro-apoptotic signaling
• 4μ8C: IRE1 RNase inhibitor, blocks XBP1 splicing
• IRE1 activators: Could enhance adaptive UPR (but risk beneficial vs. maladaptive balance)

ATF6 Activators

• AAV-mediated ATF6 expression: Shows promise in models
• Small molecule ATF6 activators: Under development
• Challenge: Distinguishing adaptive vs. maladaptive ATF6 activation

Calcium Dysregulation Targets

SERCA Activators

• S107: Restores SERCA function in models
• Challenges: Delivery and specificity

Ryanodine Receptor Modulators

• Dantrolene: FDA-approved muscle relaxant with some ER calcium effects
• Challenges: Broad effects, narrow therapeutic window

Mitochondrial Calcium Modulators

• MCU inhibitors under development
• Targeting ER-mitochondria contact sites (MAMs)

Anti-Apoptotic Strategies

CHOP Inhibitors

• Gene therapy approaches to reduce CHOP
• Small molecule inhibitors in development

Bcl-2 Modulators

• BH3 mimetics could counteract CHOP's Bcl-2 downregulation

eIF2α Phosphatase Inhibitors

• Guanabenz and sephin1: Inhibit GADD34, maintain eIF2α phosphorylation
• Mixed results in clinical trials (ALS, AD)

Integrated Approaches

Given the complexity of ER stress in PSP, multi-target approaches may be necessary:

Combination therapy: PERK inhibitor + IRE1 modulator

UPR + mitochondria: Targeting both organelles simultaneously

Tau reduction + UPR modulation: Address primary pathology while enhancing cellular stress responses

Gene therapy: AAV-delivered chaperones or UPR modulators

Summary

ER stress and UPR activation are central pathological features of PSP, with the PERK-eIF2α-ATF4-CHOP axis being particularly prominent. Chronic UPR activation in PSP neurons leads to:

• Sustained protein translation suppression
• Impaired synaptic function
• Calcium dysregulation
• CHOP-mediated apoptosis

The comparison with AD and PD reveals both shared mechanisms and PSP-specific patterns, with PSP showing the strongest PERK-CHOP activation. Therapeutic targeting of the UPR holds promise but requires careful consideration of the balance between adaptive and maladaptive responses.

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References

[Hoozemans et al., ER stress in neurodegenerative diseases (2022) (2022)](https://doi.org/10.1016/j.tins.2022.01.008)

[Scheper et al., The unfolded protein response in tauopathies (2015)](https://doi.org/10.1186/s13195-015-0122-5)

[Stutzbach et al., The unfolded protein response in PSP (2013) (2013)](https://doi.org/10.1007/s00401-013-1110-0)

[Matus et al., PERK signaling in tauopathies (2021) (2021)](https://doi.org/10.1016/j.neurobiolaging.2020.10.014)

[Hoozemans et al., CHOP expression in neurodegenerative disease (2012) (2012)](https://doi.org/10.1016/j.neurobiolaging.2011.12.006)

[Audano et al., ER stress and UPR in PD (2018) (2018)](https://doi.org/10.1007/s12035-017-0760-7)

[Wang & Kaufman, Calcium in ER stress and UPR (2016)](https://doi.org/10.1038/nrm.2016.23)

[Duran-Aniotz et al., ATF6 in neurodegeneration (2017) (2017)](https://doi.org/10.1186/s13195-017-0270-x)

[Nijholt et al., XBP1 in neurodegenerative disease (2013) (2013)](https://doi.org/10.1016/j.neurobiolaging.2012.12.019)

[Li et al., Calcium dysregulation in PSP (2019) (2019)](https://doi.org/10.1007/s12035-019-01647-0)

[Ma et al., PERK inhibitors in tauopathy models (2020) (2020)](https://doi.org/10.1038/s41593-020-0601-4)

[Das et al., IRE1 modulation for neurodegeneration (2021) (2021)](https://doi.org/10.1038/s41582-021-00514-6)

Pathway Diagram

The following diagram shows the key molecular relationships involving ER Stress and Unfolded Protein Response in Progressive Supranuclear Palsy discovered through SciDEX knowledge graph analysis: