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Unfolded Protein Response (UPR)

Introduction

Unfolded Protein Response (Upr) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

...

Unfolded Protein Response (UPR)

Introduction

Unfolded Protein Response (Upr) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Mermaid diagram (expand to render)

The unfolded protein response (UPR) is an evolutionarily conserved cellular stress response activated when misfolded or unfolded proteins accumulate in the endoplasmic reticulum (ER), a condition known as ER stress. The [endoplasmic-reticulum-stress](/mechanisms/endoplasmic-reticulum-stress) is orchestrated by three ER-resident transmembrane sensor proteins — PERK (protein kinase R-like ER kinase), IRE1alpha (inositol-requiring enzyme 1alpha), and ATF6 (activating transcription factor 6) — which collectively initiate signaling cascades to restore protein homeostasis ([proteostasis). When adaptive [endoplasmic-reticulum-stress](/mechanisms/endoplasmic-reticulum-stress) mechanisms fail to resolve ER stress, the response shifts to a terminal phase that triggers [apoptosis](/mechanisms/apoptosis) and neuronal death ([Hetz & Saxena, 2017](https://doi.org/10.1038/nrneurol.2017.99)). [@walter2011]

Given that protein misfolding and aggregation are hallmarks of virtually all neurodegenerative diseases — including [alzheimers](/diseases/alzheimers-disease), [parkinsons](/diseases/parkinsons-disease), [als](/diseases/als), [huntington-pathway](/mechanisms/huntington-pathway), and [prion-diseases](/diseases/prion-diseases) — the [endoplasmic-reticulum-stress](/mechanisms/endoplasmic-reticulum-stress) has emerged as a central mechanistic link between protein pathology and neuronal death. Pharmacological modulation of [endoplasmic-reticulum-stress](/mechanisms/endoplasmic-reticulum-stress) signaling, particularly the PERK pathway, has shown potent neuroprotective effects in preclinical models. [@ma2013]

The Three UPR Branches

PERK Pathway

The PERK branch provides the earliest [endoplasmic-reticulum-stress](/mechanisms/endoplasmic-reticulum-stress) response: [@halliday2017]

Activation: Under ER stress, BiP/GRP78 (the ER chaperone that normally keeps PERK inactive) dissociates from PERK's luminal domain, allowing PERK homodimerization and autophosphorylation

eIF2α phosphorylation: Activated PERK phosphorylates eIF2α (eukaryotic initiation factor 2α), causing global translational attenuation — reducing the protein load entering the ER

ATF4 induction: Paradoxically, p-eIF2α selectively enhances translation of ATF4, a transcription factor that upregulates stress-response genes involved in amino acid metabolism, redox homeostasis, and [autophagy](/mechanisms/autophagy-lysosome-neurodegeneration)

CHOP activation: Sustained PERK signaling induces CHOP (C/EBP homologous protein, also known as DDIT3/GADD153), a pro-apoptotic transcription factor that marks the transition from adaptive to maladaptive [unfolded-protein-response](/entities/unfolded-protein-response). CHOP promotes [apoptosis](/mechanisms/apoptosis) by suppressing anti-apoptotic Bcl-2, activating ER oxidase ERO1α (generating [oxidative-stress](/mechanisms/oxidative-stress), and inducing GADD34 (which dephosphorylates eIF2α, restoring translation of misfolded proteins in a toxic positive feedback loop)

IRE1α Pathway

IRE1α is the most evolutionarily ancient UPR sensor: [@moreno2013]

Activation: Similar to PERK, BiP dissociation triggers IRE1α oligomerization and trans-autophosphorylation

XBP1 splicing: Activated IRE1α's endoribonuclease domain catalyzes unconventional cytoplasmic splicing of XBP1 mRNA, producing the active transcription factor XBP1s. XBP1s upregulates genes encoding ER chaperones, ERAD components, and lipid biosynthesis enzymes

RIDD: Under chronic stress, IRE1α's RNase activity shifts to Regulated IRE1-Dependent Decay (RIDD), degrading ER-localized mRNAs to reduce the protein folding burden — but also degrading essential mRNAs, contributing to cell death

ASK1/JNK activation: IRE1α recruits TRAF2 and activates ASK1-JNK signaling, promoting apoptosis and [neuroinflammation](/mechanisms/neuroinflammation) via [nf-kb](/entities/nf-kb)

ATF6 Pathway

ATF6 provides a transcriptional boost to ER folding capacity: [@krukowski2020]

Activation: Under ER stress, ATF6 (a type II transmembrane protein) is transported from ER to Golgi

Proteolytic processing: In the Golgi, Site-1 and Site-2 proteases cleave ATF6, releasing its cytoplasmic N-terminal bZIP transcription factor domain

Target genes: ATF6 translocates to the nucleus and upregulates ER chaperones (BiP, GRP94, calnexin), ERAD components, and XBP1 (amplifying the IRE1α pathway)

UPR in Neurodegenerative Diseases

Alzheimer's Disease

UPR activation markers (phosphorylated PERK, p-eIF2α, activated IRE1α) are elevated in AD brain tissue, particularly in the [hippocampus](/brain-regions/hippocampus) and [cortex](/brain-regions/cortex). Key connections include: [@hoozemans2009]

[amyloid-beta](/proteins/amyloid-beta) oligomers induce ER stress and PERK activation in [neurons](/entities/neurons)
[tau-protein](/proteins/tau) hyperphosphorylation is promoted by PERK-mediated translational changes
[psen1](/genes/psen1) mutations (causing familial AD) disrupt ER calcium homeostasis, exacerbating ER stress
eIF2α phosphorylation impairs synaptic plasticity and [long-term-potentiation](/mechanisms/long-term-potentiation), contributing to memory deficits ([Ma et al., 2013](https://doi.org/10.1016/j.neuron.2013.03.025))

Parkinson's Disease

[alpha-synuclein](/proteins/alpha-synuclein) oligomers directly bind to and activate IRE1α and PERK
ER-mitochondria calcium transfer disruption (via MAMs is a key mechanism
[pink1](/proteins/pink1-protein) and [prkn](/genes/prkn) interact with UPR components; PINK1 deficiency sensitizes [neurons](/entities/neurons) to ER stress
[lrrk2](/proteins/lrrk2-protein) mutations impair ER-Golgi trafficking, triggering UPR

ALS/FTD

[tdp-43](/proteins/tdp-43) cytoplasmic aggregation activates PERK and IRE1α
[sod1-protein](/proteins/sod1-protein) mutant protein aggregates overwhelm ER quality control
[c9orf72](/genes/c9orf72) dipeptide repeat proteins cause ER stress through nucleocytoplasmic transport defects
[fus](/entities/fus) mutations disrupt ER-associated protein processing

Prion Diseases

Prion protein (PrPSc) accumulation triggers sustained PERK activation
The PERK-eIF2α-ATF4-CHOP pathway is a major driver of prion-induced neurodegeneration
Genetic or pharmacological inhibition of PERK signaling is profoundly neuroprotective in prion-infected mice ([Moreno et al., 2012](https://doi.org/10.1038/nature11825))

Huntington's Disease

Mutant [huntingtin](/proteins/huntingtin) protein disrupts ERAD, causing ER stress
XBP1s overexpression is neuroprotective in HD models
IRE1α-mediated RIDD degrades essential neuronal mRNAs

Therapeutic Targeting

PERK Pathway Modulation

The PERK-eIF2α axis has emerged as the most promising therapeutic target within the UPR: [@hetz2014]

GSK2606414: First selective PERK inhibitor; showed potent neuroprotection in prion-infected mice but caused pancreatic toxicity
ISRIB (Integrated Stress Response Inhibitor): Acts downstream of eIF2α phosphorylation; restores translation without inhibiting PERK directly. Shows broad neuroprotective effects and cognitive enhancement in aged mice ([Krukowski et al., 2020](https://doi.org/10.7554/eLife.62048)). Currently in clinical development.
Trazodone hydrochloride: Existing antidepressant that acts downstream of p-eIF2α; neuroprotective in prion and FTD mouse models ([Halliday et al., 2017](https://doi.org/10.1093/brain/awx074))
Salubrinal: Inhibits eIF2α dephosphorylation; mixed results (protective vs. toxic depending on context)

IRE1α Modulators

4μ8C and STF-083010: IRE1α RNase inhibitors; under preclinical investigation
KIRA6: Kinase-inhibiting RNase attenuator; protects retinal [neurons](/entities/neurons) from ER stress

Chaperone-Based Therapies

4-PBA (sodium phenylbutyrate): Chemical chaperone that reduces ER stress; component of AMX0035 (Relyvrio) for ALS
TUDCA (tauroursodeoxycholic acid): Bile acid derivative with chemical chaperone properties; also a component of AMX0035
Arimoclomol: Co-inducer of [heat shock proteins](/entities/heat-shock-proteins); amplifies the chaperone response

Animal Models

Key animal studies have established the therapeutic relevance of UPR modulation: [@remondelli2017]

Prion-infected mice: PERK inhibition with GSK2606414 completely prevented neurodegeneration but caused pancreatic toxicity; ISRIB partially restored translation without pancreatic effects5,6</a>
rTg4510 [tau](/proteins/tau) mice: Chronic PERK-eIF2α activation contributes to translational repression and synapse loss; ISRIB restores memory function
SOD1-G93A ALS mice: ISRIB fine-tunes UPR, improving motor neuron survival by maintaining protective ATF4 signaling while reducing translational block[@bugallo2020]
5xFAD AD mice: Genetic reduction of PERK rescues synaptic plasticity and spatial memory deficits
Aged wild-type mice: ISRIB restores cognitive function in aged mice, reversing age-related translational decline[@krukowski2020]

Clinical Development (2024-2025 Updates)

Two major clinical programs testing eIF2B activators (ISRIB mechanism) reported results in 2025: [@moreno2012]

DNL343 (Denali Therapeutics): A CNS-penetrant eIF2B activator tested in the Healy ALS Platform Trial. In January 2025, DNL343 failed to meet primary and key secondary endpoints — it did not change [neurofilament light](/biomarkers/neurofilament-light-chain-nfl) chain levels after 6 months of treatment or in a 7-month open-label extension[@green2025]
Fosigotifator (Calico/AbbVie): Another eIF2B activator tested in ALS. Also failed to meet the primary endpoint of slowing ALS progression in January 2025, with no effect on respiratory function or quality of life endpoints
Trazodone + dibenzoylmethane: Existing drugs acting downstream of p-eIF2α showed neuroprotection in prion and FTD mice; trazodone repurposing is under investigation for neurodegenerative applications[@halliday2017]
AMX0035 (Relyvrio): Combination of 4-PBA + TUDCA (chemical chaperones reducing ER stress) was FDA-approved for ALS in 2022 but withdrawn in 2024 after Phase 3 PHOENIX trial failed to confirm efficacy

These clinical setbacks highlight that while preclinical UPR modulation is profoundly neuroprotective, translating these findings to human neurodegenerative disease remains challenging, possibly due to differences in disease stage, pathway redundancy, or the difficulty of achieving appropriate pathway modulation in the human CNS. [@bugallo2020]

Brain Atlas Resources

Allen Human Brain Atlas: [Unfolded Protein Response expression search](https://human.brain-map.org/microarray/search/show?search_term=Unfolded+Protein+Response)
Allen Mouse Brain Atlas: [Unfolded Protein Response search](https://mouse.brain-map.org/search/index.html?query=Unfolded+Protein+Response)
Allen Cell Type Atlas: [Transcriptomic cell type reference](https://portal.brain-map.org/atlases-and-data/rnaseq)
BrainSpan Developmental Transcriptome: [Unfolded Protein Response developmental expression](https://www.brainspan.org/rnaseq/search/index.html?search_term=Unfolded+Protein+Response)
[Researchers Index — All researchers](/genes/ar)
[Diseases Index — Disease overview pages](/companies/overview)

External Links

[Google Scholar](https://scholar.google.com) — Publications
[PubMed](https://pubmed.ncbi.nlm.nih.gov) — Biomedical literature

Background

The study of Unfolded Protein Response (Upr) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development. [@green2025]

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions. [@stress]

Additional evidence sources: [@protein] [@autophagy] [@proteinaggregation] [@alzheimers] [@priondisease] [@als] [@isrib] [@dnl] [@upr]

References

[Unknown, Hetz C, Saxena S (2017). ER stress and the unfolded protein response in neurodegeneration. Nature Reviews Neurology, 13(8):477-491. [DOI (2017)](https://doi.org/10.1038/nrneurol.2017.99)

[Unknown, Walter P, Ron D (2011). The unfolded protein response: from stress pathway to homeostatic regulation. Science, 334(6059):1081-1086. [DOI (2011)](https://doi.org/10.1126/science.1209038)

[Ma T, Trinh MA, Bhatt AJ, et al., (2013). Suppression of eIF2α kinases alleviates Alzheimer's Disease-related plasticity and memory deficits. Nature Neuroscience, 16(9):1299-1305. [DOI (2013)](https://doi.org/10.1038/nn.3486)

[Halliday M, Radford H, Zents KAM, et al., (2017). Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain, 140(6):1768-1783. [DOI (2017)](https://doi.org/10.1093/brain/awx074)

[Moreno JA, Halliday M, Molloy C, et al., (2013). Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Science Translational Medicine, 5(206):206ra138. [DOI (2013)](https://doi.org/10.1126/scitranslmed.3006767)

[Krukowski K, Nolan A, Frias ES, et al., (2020). Small molecule cognitive enhancer reverses age-related memory decline in mice. eLife, 9:e62048. [DOI (2020)](https://doi.org/10.7554/eLife.62048)

[Hoozemans JJ, van Haastert ES, Eikelenboom P, et al., (2009). Activation of the unfolded protein response in Alzheimer's Disease. American Journal of Pathology, 174(4):1241-1251. [DOI (2009)](https://doi.org/10.2353/ajpath.2009.080814)

[Unknown, Hetz C, Mollereau B (2014). Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nature Reviews Neuroscience, 15(4):233-249. [DOI (2014)](https://doi.org/10.1038/nrn3689)

[Unknown, Remondelli P, Bhatt A (2017). The endoplasmic reticulum unfolded protein response in neurodegenerative disorders and its potential therapeutic significance. Frontiers in Molecular Neuroscience, 10:187. [DOI (2017)](https://doi.org/10.3389/fnmol.2017.00187)

[Moreno JA, Radford H, Peretti D, et al., (2012). Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature, 485(7399):507-511. [DOI (2012)](https://doi.org/10.1038/nature11058)

[Bugallo R, et al., (2020). Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis. Cell Death & Disease, 11(5):397. [DOI (2020)](https://doi.org/10.1038/s41419-020-2601-2)

[Green H, et al. (2025). Investigational eIF2B activator DNL343 modulates the integrated stress response in preclinical models of, tdp-43 pathology and individuals with ALS in a randomized clinical trial. Nature Communications, 16:4482. [DOI (2025)](https://doi.org/10.1038/s41467-025-63031-y)

Unknown, - [ER Stress in Neurodegeneration] — Related mechanism page (n.d.)

Unknown, - [Protein Quality Control] — Broader proteostasis network (n.d.)

Unknown, - autophagy — Complementary protein clearance pathway (n.d.)

Unknown, - protein-aggregation — Trigger for UPR activation (n.d.)

Unknown, - alzheimers — Major disease with UPR involvement (n.d.)

Unknown, - prion-disease — Disease where UPR targeting is most validated (n.d.)

Unknown, - als — Clinical trial target for UPR modulators## External Links (n.d.)

-, ISRIB — Alzforum (n.d.)

-, DNL343 — Alzforum (n.d.)

-, UPR pathway — KEGG (n.d.)

Pathway Diagram

The following diagram shows the key molecular relationships involving upr discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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📊 Evidence Profile Foundational

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upr

Unfolded Protein Response (UPR)

Introduction

Overview

Unfolded Protein Response (UPR)

Introduction

Overview

The Three UPR Branches

PERK Pathway

IRE1α Pathway

ATF6 Pathway

UPR in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

ALS/FTD

Prion Diseases

Huntington's Disease

Therapeutic Targeting

PERK Pathway Modulation

IRE1α Modulators

Chaperone-Based Therapies

Animal Models

Clinical Development (2024-2025 Updates)

Brain Atlas Resources

External Links

Background

References

Pathway Diagram

💬 Discussion