Unfolded Protein Response (UPR)

Unfolded Protein Response (UPR)

Introduction

The unfolded protein response (UPR) is a conserved intracellular signaling network activated when misfolded or unfolded proteins accumulate in the endoplasmic reticulum (ER) lumen, a condition termed ER stress. Under normal conditions, the UPR restores proteostasis by reducing protein synthesis, upregulating ER chaperones, and enhancing ER-associated degradation (ERAD). However, when ER stress is chronic or overwhelming—as occurs in neurodegenerative diseases where aggregation-prone proteins accumulate—the UPR shifts from a protective to a pro-apoptotic program, contributing directly to neuronal death. Dysregulated UPR signaling has been documented in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, making the UPR a central mechanistic node and therapeutic target in neurodegeneration. [@hetz2017]

Overview

What is the UPR?

The UPR represents a fundamentalcellular quality control mechanism that senses the folding environment within the ER lumen and communicates this information to the cytosol and nucleus. The ER lumen contains an extensive network of molecular chaperones, including BiP (GRP78), that assist in protein folding. Under conditions of ER stress where the load of client proteins exceeds folding capacity, BiP becomes sequestered by binding to misfolded proteins, leaving the three ER transmembrane sensors—PERK, IRE1, and ATF6—unmasked to initiate downstream signaling. [@walter2011]

Historical Context

Unfolded Protein Response (UPR)

Introduction

The unfolded protein response (UPR) is a conserved intracellular signaling network activated when misfolded or unfolded proteins accumulate in the endoplasmic reticulum (ER) lumen, a condition termed ER stress. Under normal conditions, the UPR restores proteostasis by reducing protein synthesis, upregulating ER chaperones, and enhancing ER-associated degradation (ERAD). However, when ER stress is chronic or overwhelming—as occurs in neurodegenerative diseases where aggregation-prone proteins accumulate—the UPR shifts from a protective to a pro-apoptotic program, contributing directly to neuronal death. Dysregulated UPR signaling has been documented in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, making the UPR a central mechanistic node and therapeutic target in neurodegeneration. [@hetz2017]

Overview

What is the UPR?

The UPR represents a fundamentalcellular quality control mechanism that senses the folding environment within the ER lumen and communicates this information to the cytosol and nucleus. The ER lumen contains an extensive network of molecular chaperones, including BiP (GRP78), that assist in protein folding. Under conditions of ER stress where the load of client proteins exceeds folding capacity, BiP becomes sequestered by binding to misfolded proteins, leaving the three ER transmembrane sensors—PERK, IRE1, and ATF6—unmasked to initiate downstream signaling. [@walter2011]

Historical Context

The UPR was initially characterized in yeast in the 1980s, where the IRE1 pathway was found to mediate transcriptional activation of ER chaperones. Subsequent work in mammalian cells identified all three UPR传感器 and revealed their complex, integrated roles in deciding between adaptive and apoptotic outcomes. The Nobel Prize-winning work on ER stress and the UPR has highlighted its fundamental importance in cellular homeostasis, and dysregulation of the UPR is now recognized as a key contributor to numerous human diseases, including neurodegeneration. [@gething1992]

The Three UPR Branches

1. PERK-eIF2α Pathway

The PERK (EIF2AK3) kinase is one of the three primary ER stress sensors. Under non-stress conditions, PERK is bound by BiP and maintained in an inactive state. Upon ER stress, BiP dissociation activates PERK's kinase domain, allowing it to autophosphorylate and subsequently phosphorylate the eukaryotic translation initiation factor eIF2α at Ser51. This phosphorylation causes a global translation attenuation while paradoxically permitting translation of specific mRNAs containing upstream open reading frames (uORFs), such as ATF4. [@harding2000]

ATF4 and the Integrated Stress Response

ATF4 is a transcription factor that drives expression of genes involved in amino acid metabolism, antioxidant responses, and autophagy. Under prolonged ER stress, ATF4 alsoupregulates CHOP (DDIT3), a pro-apoptotic transcription factor that promotes cell death through multiple mechanisms. CHOP represses anti-apoptotic Bcl-2 family proteins, induces GADD34 (PPP1R15A) to dephosphorylate eIF2α (creating a negative feedback loop), and promotes oxidative stress. The PERK-CHOP axis is critically important in determining whether cells survive or undergo apoptosis during ER stress. [@novoa2001]

2. IRE1-XBP1 Pathway

IRE1 (ERN1) is a dual-function protein containing a serine/threonine kinase domain and an endoribonuclease domain. Activation of IRE1 by ER stress causes dimerization and autophosphorylation, which activates its RNase activity. The key substrate of activated IRE1 is XBP1 mRNA, which undergoes unconventional splicing to produce XBP1s (spliced XBP1), a potent transcription factor. [@calfon2002]

XBP1s Target Genes

XBP1s drives expression of numerous target genes including:

• ER chaperones: BiP (HSPA5), GRP94 (HSP90B1), PDI family members
• ERAD components: EDEM1, SEL1L, Herp (UBAC1)
• Lipid synthesis genes: XBP1 also regulates lipid metabolism
• Autophagy genes: IRE1-independent functions also emerge

3. ATF6 Pathway

ATF6 (ATF6A) is a type II transmembrane transcription factor that localizes to the ER membrane under non-stress conditions. Upon ER stress, ATF6 translocates to the Golgi apparatus where it is cleaved by proteases S1P and S2P, releasing the cytosolic domain (ATF6f) that functions as a transcription factor. ATF6f activates genes involved in protein folding, ERAD, and lipid biosynthesis, complementing the PERK and IRE1 pathways. [@haze2019]

ATF6 Isoforms

Mammals express two isoforms, ATF6α (ATF6) and ATF6β (ATF6B), with overlapping but distinct functions. ATF6α is the primary functionally relevant isoform in the UPR, while ATF6β appears to play more of a modulatory role. ATF6 has gained attention as a potential therapeutic target because its activation does not involve the pro-apoptotic outputs of PERK and IRE1, making it potentially safer to pharmacologically enhance.

Signaling Integration

The three UPR branches do not operate in isolation but are integrated at multiple levels:

The decision point between adaptive and apoptotic UPR outcomes is determined by the intensity and duration of ER stress, the cell's metabolic state, and the balance between pro-survival and pro-death signals from all three branches. [@hetz2023]

UPR in Neurodegenerative Diseases

Alzheimer's Disease

ER stress and UPR activation are prominent features of AD pathophysiology: [@ma2013]

• Aβ toxicity: Amyloid-β oligomers induce ER stress in neurons
• Tau pathology: Hyperphosphorylated tau impairs ER function
• CHOP expression: Elevated in AD brain, correlating with disease severity
• PERK activation: Phospho-PERK and phospho-eIF2α found in AD brains
• XBP1 dysregulation: Impaired XBP1 splicing in AD neurons

Parkinson's Disease

PD shows selective vulnerability to ER stress: [@dauer2003]

• α-Synuclein toxicity: Mutant α-synuclein causes ER stress
• PINK1/Parkin relationship: Mitochondrial dysfunction links to ER stress
• CHOP upregulation: Dopaminergic neurons show high CHOP expression
• XBP1 variants: Genetic variants in XBP1 associated with PD risk
• ER-mitochondrial contacts: Disruption of MAMs in PD

Amyotrophic Lateral Sclerosis (ALS)

UPR activation is a consistent finding in ALS: [@saxena2013]

• TDP-43 pathology: Cytoplasmic TDP-43 aggregates cause ER stress
• SOD1 mutations: Mutant SOD1 triggers all three UPR branches
• C9orf72 expansions: Dipeptide repeat proteins induce ER stress
• FUS pathology: RNA-binding protein aggregates disrupt ER function
• CHOP deletion: Protective in ALS mouse models

Huntington's Disease

HD shows ER stress involvement: [@orr2002]

• Mutant huntingtin: Impairs ER function and calcium homeostasis
• XBP1 splicing: Dysregulated in HD models
• CHOP involvement: Contributes to striatal neuron death
• PERK-eIF2α: Overactivated, contributing to translation defects

Frontotemporal Dementia

FTD, particularly the TDP-43 pathology forms, involves UPR: [@rascovsky2021]

• TDP-43 inclusions: Cytoplasmic aggregates cause ER stress
• CHOP elevation: Observed in FTD brain tissue
• ATF4 dysregulation: Implicated in FTD pathogenesis

Mechanism of UPR-Mediated Neuronal Death

Apoptotic Pathways

The UPR promotes neuronal death through multiple pathways:

1. CHOP-Mediated Apoptosis

CHOP is the primary executor of UPR-induced apoptosis. Its pro-death functions include: [@gorman2007]

• Repression of Bcl-2, promoting mitochondrial outer membrane permeabilization
• Upregulation of GADD34, leading to eIF2α dephosphorylation and protein synthesis overload
• Induction of DR5 (TNFRSF10B), death receptor upregulation
• ROS production through CHOP-target genes

2. IRE1-Mediated Cell Death

Prolonged IRE1 activation triggers death pathways:

• ASK1-JNK pathway: IRE1 recruits ASK1 and TRAF2, activating JNK
• RIDD: IRE1 degrades random mRNAs, causing cell damage
• Bim activation: JNK phosphorylates Bim, promoting pro-apoptotic activity

3. Calcium Dysregulation

ER stress disrupts calcium homeostasis:

• Store depletion: ER calcium released during stress
• Mitochondrial calcium overload: Leads to mitochondrial permeability transition
• Calpain activation: Calcium-dependent proteases promote apoptosis

Non-Apoptotic Cell Death

Neurons can also die through non-apoptotic mechanisms:

• Ferroptosis: Iron-dependent lipid peroxidation
• Necrosis: Uncontrolled cell death
• Autophagic cell death: Excessive autophagy leading to cell death

Therapeutic Implications

UPR Modulation Strategies

| Target | Approach | Therapeutic Agent | Status |
|--------|----------|------------------|--------|
| PERK | Inhibition | GSK2656157 | Preclinical |
| IRE1 | Inhibition | MKC8866, 4μ8C | Preclinical |
| eIF2α | Dephosphorylation | ISRIB | Preclinical |
| CHOP | Inhibition | Small molecules | Early development |
| ATF6 | Activation | AAV vectors | Preclinical |
| ER chaperones | Enhancement | Bix, etc. | Clinical trials |

Small Molecule Modulators

• ISRIB (Integrated Stress Response Inhibitor): Stabilizes eIF2B, counteracts eIF2α phosphorylation
• Salubrinal: Selectively inhibits eIF2α dephosphorylation
• TUDCA: ER stress inhibitor with clinical trials in PD and AD
• Sodium valproate: Has been used to modulate UPR in clinical settings
• Guanabenz: Selects for eIF2α phosphorylation, tested in ALS

Gene Therapy Approaches

• XBP1 overexpression: AAV-delivered XBP1s in PD models
• CHOP shRNA: Knockdown protects neurons
• ATF6 activation: Constitutively active ATF6 variants for neuroprotection
• BiP/GRP78 upregulation: Molecular chaperone enhancement

Clinical Trials

Several clinical approaches target UPR in neurodegeneration:

• TUDCA: Phase II/III trials in PD and AD
• Sodium valproate: Studied in ALS
• Rapamycin: mTOR inhibition affects UPR
• Antioxidants: N-acetylcysteine, CoQ10 for oxidative stress

Biomarkers of UPR Activation

Clinical biomarkers for UPR include:

| Biomarker | Detection Method | Disease | Clinical Utility |
|-----------|-----------------|---------|------------------|
| CHOP mRNA | qPCR | PD, AD | Disease progression |
| XBP1 splicing | PCR | ALS, PD | Diagnostic |
| BiP/GRP78 | ELISA | Various | Nest Diagnostic |
| Phospho-eIF2α | IHC | Research | Research only |
| ATF6 cleavage | Western blot | Research | Research only |

UPR and Other Cellular Stress Responses

ER Stress and Mitochondria

The ER and mitochondria form close contacts called mitochondria-associated membranes (MAMs), which are critical for calcium signaling and lipid transfer. ER stress disrupts MAMs, leading to:

• Calcium dysregulation between organelles
• Increased ROS production
• Triggered apoptosis

UPR and Neuroinflammation

ER stress activates NF-κB and other inflammatory pathways:

• Pro-inflammatory cytokines: UPR induces IL-1β, TNF-α
• Microglial activation: ER stress in neurons triggers neuroinflammation
• Inflammasome activation: IRE1β can activate NLRP3 inflammasome

Integrated Stress Response (ISR)

The UPR is part of the broader integrated stress response (ISR), which senses various cellular stresses:

• PERK: Activated by ER stress, viral infection, amino acid deprivation
• GCN2: Activated by amino acid deprivation and ribosome stalling
• PKR: Activated by viral infection
• HRI: Activated by heme deprivation and oxidative stress

Clinical Translation

Clinical Trial Data

| Agent | Target | Phase | Status | NCT |
|-------|-------|-------|--------|-----|
| TUDCA (Tauroursodeoxycholic acid) | ER stress modulation | Phase II | Completed | NCT0298725 |
| TUDCA | ER stress modulation | Phase III | Recruiting | NCT05677620 |
| Sodium phenylbutyrate/taurursodiol (Relyvrio) | UPR modulation | Phase III | Approved (ALS) | NCT03184449 |
| ISRIB | eIF2B stabilization | Preclinical | - | - |
| GSK2606414 | PERK inhibition | Preclinical | - | - |
| MKC8866 | IRE1 inhibition | Preclinical | - | - |

TUDCA in Neurodegeneration: Tauroursodeoxycholic acid (TUDCA) has been studied in multiple neurodegenerative conditions. The Phase II study in PD (NCT0298725) showed signals of neuroprotective benefit, with larger Phase III trials now recruiting [@sanchez2019]. In ALS, the combination of sodium phenylbutyrate and taurursodiol (Relyvrio) received FDA approval based on Phase III data showing survival benefit.

PERK Inhibitors: GSK2606414 and related PERK inhibitors have shown efficacy in mouse models of prion disease and AD, reducing neuronal loss. However, PERK inhibition can cause pancreatic toxicity due to the essential role of PERK in protein folding in pancreatic beta cells. Second-generation PERK inhibitors with improved selectivity are in development.

IRE1 Modulators: IRE1 inhibitors like MKC8866 reduce both pro-survival (XBP1s) and pro-death (RIDD) activities, making the therapeutic window complex. Selective modulators that promote adaptive XBP1s while inhibiting RIDD are under development.

Biomarker Connections

| Biomarker | Detection Method | Disease | Clinical Utility |
|----------|---------------|---------|---------------|
| CHOP (DDIT3) mRNA | qPCR from blood | AD, PD, ALS | Disease progression marker |
| XBP1 splicing ratio | PCR from PBMCs | ALS, PD | Target engagement |
| BiP/GRP78 (HSPA5) | ELISA (blood/CSF) | AD, PD | Nested diagnostic |
| Phospho-eIF2α (Ser51) | Western blot | Research | Research use only |
| ATF6 cleavage | IHC | Research | Research use only |
| Exosomal UPR markers | Exosome isolation | AD, PD | Emerging biomarker |

Blood-Based Biomarkers: CHOP mRNA levels in peripheral blood mononuclear cells (PBMCs) correlate with disease severity in ALS and PD. The XBP1 splicing ratio provides a functional readouts of IRE1 activity that can be used to assess target engagement in clinical trials. Elevated BiP/GRP78 in CSF has been reported in AD and may serve as a diagnostic marker.

Imaging Biomarkers: While direct imaging of UPR activation is not yet possible, MR spectroscopy can detect elevated hippocampal glutamate in AD, which may reflect impaired protein synthesis due to eIF2α phosphorylation. PET tracers for activated microglia (e.g., TSPO) may indirectly reflect UPR-associated neuroinflammation.

Patient Impact

Disease-Modifying Potential: UPR modulators represent a genuinely disease-modifying approach rather than symptomatic treatment. By targeting the core proteostasis dysfunction in neurodegeneration, these agents could potentially slow or halt disease progression rather than merely alleviating symptoms.

Therapeutic Challenges: Several challenges limit UPR-targeted therapy development:

• Delivery across the blood-brain barrier: Many UPR modulators have poor brain penetration
• Cell type specificity: Targeting UPR in neurons without affecting peripheral organs
• Optimal timing: Intervention may need to occur before irreversible neuronal loss
• Biomarker development: Patient selection requires biomarkers to identify those with active UPR dysregulation

Open Questions

Fundamental Mechanisms

Therapeutic Challenges

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)

Molecular Chaperones and ER Proteostasis Network

BiP/GRP78: The Master Regulator

Binding immunoglobulin protein (BiP), also known as glucose-regulated protein 78 (GRP78), is the central ER chaperone that plays a pivotal role in UPR regulation. As a member of the Hsp70 family, BiP possesses ATPase activity and substrate-binding domains that enable it to recognize and fold nascent polypeptides [@lee2014]. Under normal conditions, BiP binds to the luminal domains of PERK, IRE1, and ATF6, maintaining them in an inactive state. During ER stress, BiP preferentially binds to misfolded proteins, releasing the UPR sensors to initiate signaling cascades.

The importance of BiP in neuronal survival cannot be overstated. Multiple studies have demonstrated that BiP overexpression protects neurons against various insults, including amyloid-β toxicity in Alzheimer's disease and mutant α-synuclein in Parkinson's disease [@liu2019]. Conversely, BiP deficiency leads to spontaneous ER stress and neurodegeneration in animal models.

ER Chaperone Network

Beyond BiP, the ER lumen contains a comprehensive network of chaperones and folding enzymes:

• GRP94 (HSP90B1): A ER-resident Hsp90 family chaperone that assists in folding of client proteins, particularly immunoglobulins and integrins
• Protein disulfide isomerase (PDI) family: Comprises over 20 members in humans, catalyzing disulfide bond formation and isomerization
• Calnexin/calreticulin: Lectin chaperones that assist in folding of N-glycosylated proteins
• ERp57, ERp72: Additional PDI family members with specialized functions

UPR in Specific Neuronal Populations

Dopaminergic Neurons

Dopaminergic neurons in the substantia nigra pars compacta exhibit particular vulnerability to ER stress. This vulnerability stems from multiple factors: their high metabolic demand due to pacemaking activity, the presence of neuromelanin granules that can sequester iron and promote oxidative stress, and the expression of proteins with high aggregation propensity [@dua2023].

In Parkinson's disease, dopaminergic neurons show:

• Elevated CHOP expression compared to other brain regions
• Impaired XBP1 splicing efficiency
• Altered PERK-eIF2α signaling
• Enhanced activation of the IRE1-JNK apoptosis pathway

Motor Neurons

Motor neurons in ALS exhibit pronounced UPR activation, with all three branches consistently engaged:

• PERK pathway: Phospho-PERK and phospho-eIF2α are elevated in spinal cord motor neurons
• IRE1 pathway: Persistent IRE1 activation leads to JNK-mediated apoptosis
• ATF6 pathway: ATF6 cleavage products are detected in ALS tissue

Cortical and Hippocampal Neurons

In Alzheimer's disease, cortical and hippocampal neurons show distinctive UPR patterns:

• Early adaptive UPR with XBP1s and ER chaperone upregulation
• Progression to chronic UPR with sustained PERK activation
• Eventual shift toward pro-apoptotic signaling with CHOP elevation

genetic_forms_neurodegeneration

Monogenic Forms with UPR Involvement

Several genetic forms of neurodegenerative diseases directly implicate UPR pathways:

Alzheimer's disease:

• APP duplications lead to increased Aβ production and ER stress
• PSEN1 and PSEN2 mutations affect ER calcium homeostasis
• APOE4 allele carriers show impaired UPR adaptive capacity

• LRRK2 mutations cause ER stress through unknown mechanisms
• GBA1 (glucocerebrosidase) mutations disrupt ER lipid composition
• PINK1 and Parkin mutations affect ER-mitochondrial crosstalk

• SOD1 mutations trigger robust UPR activation
• C9orf72 expansions cause both ER and nucleolar stress
• FUS and TDP-43 (TARDBP) mutations disrupt RNA processing affecting UPR

Gene Expression Studies

Transcriptomic analyses of affected brain regions reveal consistent UPR gene signatures:

• CHOP (DDIT3) upregulation across AD, PD, and ALS
• XBP1 splicing dysregulation in multiple disorders
• ATF4 target gene enrichment in diseased tissue
• Correlation between UPR markers and disease severity [@mounsey2023]

Advanced Therapeutic Strategies

Novel Small Molecule Approaches

Recent drug discovery efforts have yielded promising UPR modulators:

PERK inhibitors:

• GSK2606414: First-generation PERK inhibitor showing efficacy in prion disease models
• ISRIB derivatives: Enhanced eIF2B stabilizers with improved brain penetration

• MKC8866: IRE1 RNase inhibitor that reduces RIDD activity
• Small molecule IRE1 stabilizers promoting adaptive XBP1s

• AAV-delivered constitutively active ATF6 variants
• Small molecule ATF6 activators in development

Protein-Folding Therapies

Approaches targeting ER chaperone function:

• BiP ATPase modulators: Compounds enhancing BiP activity
• PDI inhibitors/activators: Modulating disulfide bond catalysis
• Chemical chaperones: 4-PBA, TUDCA for stabilizing protein conformation
• Autophagy enhancers: Enhancing clearance of misfolded proteins [@park2024]

Combination Therapies

Given the complexity of UPR dysregulation, combination approaches show promise:

• PERK inhibitor plus eIF2B stabilizer
• XBP1 overexpression plus CHOP inhibition
• ER stress modulators plus antioxidants
• UPR targeting plus anti-inflammatory agents

Research Tools and Models

Cellular Models

• Patient-derived iPSCs: Neurons from patients with familial disease mutations
• Induced neurons (iNs): Direct conversion of fibroblasts to neurons
• Organoids: Brain organoids showing spontaneous UPR activation
• CRISPR edited cells: Isogenic lines for studying specific mutations

Animal Models

• Transgenic models: Overexpressing mutant proteins causing ER stress
• Knockout models: Deleting UPR components to assess their role
• Conditional models: Tissue-specific manipulation of UPR pathways
• Humanized models: Expressing human proteins in mouse models

Biomarker Development

Clinical biomarkers for UPR remain a significant unmet need:

• Blood XBP1 splicing: Detectable in peripheral blood mononuclear cells
• CSF BiP levels: Elevated in some neurodegenerative conditions
• Phospho-eIF2α in blood: Potential peripheral marker
• Exosomal UPR markers: Emerging as non-invasive option [@huang2024]

References (Additional)

[@lee2014]: [Lee AS. The ER chaperone BIp. Nature Reviews Molecular Cell Biology. 2014;15(8):517-528.](https://doi.org/10.1038/nrm3840)

[@liu2019]: [Liu CY, et al. Role of GRP78/BiP in neuroprotection. Cell Stress and Chaperones. 2019;24(1):17-27.](https://doi.org/10.1007/s12192-018-0094-5)

[@ellgaard2022]: [Ellgaard L, et al. The ER protein folding quality control. Annual Review of Biochemistry. 2022;91:403-424.](https://doi.org/10.1146/annurev-biochem-032620-104513)

[@dua2023]: [Dua P, et al. Dopaminergic neuron vulnerability in Parkinson's disease. Journal of Parkinson's Disease. 2023;13(2):201-216.](https://doi.org/10.3233/JPD-223500)

[@burre2022]: [Burre J, et al. ER stress in patient-derived dopaminergic neurons. Brain. 2022;145(3):1015-1028.](https://doi.org/10.1093/brain/awab430)

[@medinas2022]: [Medinas DB, et al. ALS and the Unfolded Protein Response. Neuron. 2022;110(6):943-956.](https://doi.org/10.1016/j.neuron.2021.12.018)

[@shen2024]: [Shen H, et al. Temporal progression of UPR in Alzheimer's disease. Nature Neuroscience. 2024;27(1):89-101.](https://doi.org/10.1038/s41593-023-01456-8)

[@mounsey2023]: [Mounsey K, et al. Transcriptomic UPR signatures in neurodegenerative disease. Brain Pathology. 2023;33(2):e13124.](https://doi.org/10.1111/bpa.13124)

[@park2024]: [Park HW, et al. Emerging UPR therapeutic targets. Pharmacological Reviews. 2024;76(1):123-165.](https://doi.org/10.1124/pharmrev.123.000890)

[@huang2024]: [Huang K, et al. Exosomal UPR markers. Molecular Neurodegeneration. 2024;19(1):12.](https://doi.org/10.1186/s40035-024-00401-4)

[@sanchez2019]: [Sanchez MG, et al. TUDCA for Parkinson's disease: A randomized controlled trial. Journal of Parkinson's Disease. 2019;9(3):445-454.](https://doi.org/10.3233/JPD-191392)

Pathway Diagram

Pathway Diagram

The following diagram shows the key molecular relationships involving Unfolded Protein Response (UPR) discovered through SciDEX knowledge graph analysis: