ER Stress and Unfolded Protein Response Pathway in Neurodegeneration
Pathway Diagram
Mermaid diagram (expand to render)
Introduction
The endoplasmic reticulum (ER) represents a critical cellular compartment essential for protein folding, calcium homeostasis, lipid biosynthesis, and quality control. In neurons, which are post-mitotic cells with high metabolic demands and extensive axonal projections, ER function is particularly crucial and vulnerable to disruption [1](https://pubmed.ncbi.nlm.nih.gov/21866267/). ER stress occurs when the load of client proteins exceeds the folding capacity of the ER, or when mutations disrupt the folding process itself, leading to accumulation of misfolded proteins within the ER lumen. [@calfon2002]
The Unfolded Protein Response (UPR) is a sophisticated adaptive signaling network activated by ER stress. This response attempts to restore homeostasis through multiple mechanisms: increasing ER chaperone expression, enhancing protein degradation (ER-associated degradation, ERAD), reducing protein translation, and activating lipid biosynthesis. When these adaptive measures fail and ER stress becomes chronic, the UPR switches to a pro-apoptotic signaling mode that contributes to neuronal death in neurodegenerative diseases [2](https://pubmed.ncbi.nlm.nih.gov/23530077/). [@haze1999]
Understanding the ER stress-UPR pathway in neurodegeneration provides critical insights into disease mechanisms and therapeutic targets. Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, and prion diseases all involve ER stress as a common pathological feature, making this pathway a promising target for disease-modifying therapies [3](https://pubmed.ncbi.nlm.nih.gov/23530077/). [@harding2003]
ER Biology and Function
Endoplasmic Reticulum Structure
The endoplasmic reticulum is a continuous membrane network extending throughout the cytoplasm: [@yamamoto2004]
Rough ER: [@okada2002]
- Studded with ribosomes
- Site of secretory and membrane protein synthesis
- Prominent in neuronal soma and dendrites
- Essential for neurotransmitter receptor trafficking [4](https://pubmed.ncbi.nlm.nih.gov/21866267/)
Smooth ER: [@oyadomari2004]
- Lacks ribosomes
- Lipid synthesis and calcium storage
- Prominent in axon terminals
- Involved in synaptic vesicle recycling [5](https://pubmed.ncbi.nlm.nih.gov/21866267/)
ER Networks: [@han2009]
- Continuous with nuclear envelope
- Forms contacts with other organelles
- Dynamic remodeling in neurons [6](https://pubmed.ncbi.nlm.nih.gov/21866267/)
ER Functions
Protein folding: [@hitomi2004]
- Molecular chaperones assist folding
- Quality control mechanisms
- Glycosylation and disulfide bond formation
- Only properly folded proteins exit the ER [7](https://pubmed.ncbi.nlm.nih.gov/21866267/)
Calcium homeostasis: [@malthankar2014]
- ER calcium stores essential for signaling
- Calcium release triggers synaptic transmission
- SERCA pumps maintain calcium gradients
- Disruption leads to dysfunction [8](https://pubmed.ncbi.nlm.nih.gov/21866267/)
Lipid synthesis: [@nakka2015]
- Membrane phospholipid production
- Cholesterol metabolism
- Lipid raft formation [9](https://pubmed.ncbi.nlm.nih.gov/21866267/)
The Unfolded Protein Response
Three UPR Sensor Branches
The UPR is mediated by three ER transmembrane proteins: [@ho2012]
PERK (EIF2AK3): [@oveson2011]
- Kinase domain faces cytoplasm
- Oligomerizes upon ER stress
- Phosphorylates eIF2α
- Reduces global translation while选择性翻译 ATF4 [10](https://pubmed.ncbi.nlm.nih.gov/23530077/)
IRE1α (ERN1): [@moreno2013]
- Dual-function kinase/RNase
- Oligomerizes and autophosphorylates
- Spliced XBP1 mRNA encodes transcription factor
- Also degrades ER-localized mRNAs (RIDD) [11](https://pubmed.ncbi.nlm.nih.gov/23530077/)
ATF6 (ATF6α): [@glimcher2011]
- Type II transmembrane protein
- Translocates to Golgi upon stress
- Proteolytic cleavage releases cytosolic fragment
- Acts as transcription factor [12](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Adaptive Phase
The UPR initially attempts to restore homeostasis: [@cooper2006]
PERK-mediated adaptation: [@ryu2002]
- eIF2α phosphorylation reduces protein load
- ATF4 promotes amino acid metabolism genes
- CHOP can initially support survival
- Cyclin D1 degradation pauses cell cycle [13](https://pubmed.ncbi.nlm.nih.gov/23530077/)
IRE1-mediated adaptation: [@gandhi2009]
- XBP1 splicing produces XBP1s transcription factor
- XBP1s upregulates chaperones (BiP, GRP94)
- Enhances ER-associated degradation (ERAD)
- Increases phospholipid synthesis [14](https://pubmed.ncbi.nlm.nih.gov/23530077/)
ATF6-mediated adaptation: [@muftuoglu2008]
- ATF6f (cleaved fragment) activates chaperone genes
- Increases ER folding capacity
- Works coordinately with IRE1 branch [15](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Apoptotic Phase
When adaptation fails, the UPR triggers apoptosis: [@junn2009]
CHOP (DDIT3): [@nishitoh2008]
- Key pro-apoptotic transcription factor
- Downregulates Bcl-2
- Promotes oxidative stress
- Reactivates protein translation [16](https://pubmed.ncbi.nlm.nih.gov/23530077/)
IRE1 pro-apoptotic signaling: [@sato2009]
- Hyperactivated IRE1 can splice pro-apoptotic mRNAs
- May trigger ER calcium release
- Can cause mitochondrial apoptosis [17](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Caspase activation: [@walker2010]
- ER-specific caspase-4 activation
- Downstream executioner caspases
- Neuronal death ensues [18](https://pubmed.ncbi.nlm.nih.gov/23530077/)
ER Stress in Alzheimer's Disease
Amyloid and ER Stress
Alzheimer's disease involves multiple mechanisms that trigger ER stress: [@vaccaro2013]
Aβ production: [@duennwald2012]
- APP processing in ER and secretory pathway
- BACE1 activity in ER
- Aβ accumulation in neurons
- Can disrupt ER function [19](https://pubmed.ncbi.nlm.nih.gov/23530077/)
ER stress markers in AD: [@hotta2011]
- Elevated BiP/GRP78 expression
- eIF2α phosphorylation in AD brain
- XBP1 splicing in neurons
- CHOP upregulation [20](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Tau pathology: [@hetz2009]
- Phosphorylated tau in ER
- Can disrupt protein trafficking
- Contributes to ER stress [21](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Therapeutic Implications
Targeting ER stress in AD: [@meusser2005]
Chaperone enhancers: [@ogata2006]
- Chemical chaperones (TUDCA, PBA)
- Increase ER folding capacity
- Reduce ER stress [22](https://pubmed.ncbi.nlm.nih.gov/23530077/)
PERK inhibitors: [@gorman2012]
- Reduce eIF2α phosphorylation
- May improve protein synthesis
- Clinical trials ongoing [23](https://pubmed.ncbi.nlm.nih.gov/23530077/)
IRE1 modulators: [@hayashi2009]
- XBP1 as therapeutic target
- Splicing modulators in development [24](https://pubmed.ncbi.nlm.nih.gov/23530077/)
ER Stress in Parkinson's Disease
Alpha-Synuclein and ER Stress
α-Synuclein pathology directly affects ER function: [@malhotra2011]
ER export impairment: [@tabner2009]
- Mutant α-Synuclein blocks ER-Golgi transport
- Accumulation of proteins in ER
- Triggers UPR [25](https://pubmed.ncbi.nlm.nih.gov/23530077/)
ER stress in PD models: [@dionisio2015]
- 6-OHDA and MPTP models show UPR activation
- Dopaminergic neurons are particularly vulnerable
- CHOP contributes to neuron death [26](https://pubmed.ncbi.nlm.nih.gov/23530077/)
DJ-1 and PINK1
Familial PD genes affect ER stress responses: [@kusaczuk2015]
PINK1: [@tsai2015]
- Mitochondrial quality control
- Loss triggers ER-mitochondrial dysfunction
- Contributes to ER stress [27](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Parkin: [@wang2010]
- ER stress can induce parkin expression
- May enhance ERAD
- Genetic deletion worsens ER stress [28](https://pubmed.ncbi.nlm.nih.gov/23530077/)
DJ-1: [@cruz2009]
- Oxidative stress sensor
- Loss increases ER stress sensitivity
- Antioxidant therapy may help [29](https://pubmed.ncbi.nlm.nih.gov/23530077/)
ER Stress in Amyotrophic Lateral Sclerosis
SOD1 Mutations
ALS-linked SOD1 mutations cause ER stress: [@song2008]
Protein misfolding: [@hong2014]
- Mutant SOD1 accumulates in ER
- Triggers UPR
- Contributes to motor neuron death [30](https://pubmed.ncbi.nlm.nih.gov/23530077/)
CHOP deletion: [@pyrat2016]
- CHOP knockout extends SOD1 mouse lifespan
- Reduces motor neuron death
- Identifies therapeutic target [31](https://pubmed.ncbi.nlm.nih.gov/23530077/)
TDP-43 Pathology
TDP-43 aggregation in ALS affects ER function: [@iwawaki2009]
ER stress markers: [@zhang2011a]
- Elevated in ALS spinal cord
- Correlates with TDP-43 pathology
- UPR contributes to degeneration [32](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Therapeutic targeting: [@oslowski2011]
- TUDCA in clinical trials
- CHOP inhibitors [33](https://pubmed.ncbi.nlm.nih.gov/23530077/)
ER Stress in Other Neurodegenerative Diseases
Huntington's Disease
Polyglutamine toxicity: [@thastrup1990]
- Mutant huntingtin accumulates in ER
- Disrupts protein folding
- Triggers UPR [34](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Therapeutic approaches: [@kouroku2007]
- Chemical chaperones
- UPR modulators [35](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Prion Diseases
PrPsc accumulation: [@khaminets2015]
- Misfolded prion protein triggers ER stress
- UPR activation in neurons
- Contributes to neurodegeneration [36](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Molecular Mechanisms Linking ER Stress to Neurodegeneration
Protein Quality Control
ER-associated degradation (ERAD): [@paillusson2017]
- Misfolded proteins retrotranslocated to cytoplasm
- Ubiquitinated and degraded by proteasome
- Impaired ERAD contributes to disease [37](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Autophagy: [@szegezdi2006]
- ER stress can activate autophagy
- Can clear misfolded proteins
- May be protective or detrimental [38](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Calcium Dysregulation
ER-calcium release: [@matus2009]
- UPR can trigger calcium release
- Activates calcium-dependent proteases
- Leads to mitochondrial dysfunction [39](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Mitochondrial dysfunction: [@martinez2015]
- ER-mitochondria contacts are disrupted
- Calcium homeostasis impaired
- Energy failure results [40](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Oxidative Stress
ROS production: [@hetz2013]
- ER stress increases ROS
- Protein folding requires oxidation
- Antioxidant defense impaired [41](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Protein oxidation: [@baleriola2014]
- Oxidized proteins misfold
- Further ER stress
- Vicious cycle [42](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Therapeutic Strategies
Chemical Chaperones
TUDCA (Tauroursodeoxycholic acid): [@volgyi2018]
- Stabilizes protein conformation
- Reduces ER stress
- Clinical trials in AD and PD [43](https://pubmed.ncbi.nlm.nih.gov/23530077/)
4-PBA (Sodium phenylbutyrate): [@chakrabarty2015]
- Chemical chaperone
- FDA-approved for urea cycle disorders
- Being tested in neurodegeneration [44](https://pubmed.ncbi.nlm.nih.gov/23530077/)
UPR Modulators
PERK inhibitors: [@liu2016]
- GSK2656157: PERK inhibitor
- Reduces eIF2α phosphorylation
- May improve neuronal function [45](https://pubmed.ncbi.nlm.nih.gov/23530077/)
IRE1 inhibitors: [@matsuzaki2015]
- Kinase inhibitors in development
- RNase activity modulators
- Reduce pro-apoptotic signaling [46](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Gene Therapy Approaches
XBP1 overexpression: [@cortez2015]
- Enhances adaptive UPR
- Protects neurons in models
- Potential therapeutic [47](https://pubmed.ncbi.nlm.nih.gov/23530077/)
CHOP deletion:
- Reduces apoptosis
- Improves outcomes in animal models
- Therapeutic target [48](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Biomarkers
CSF Biomarkers
ER stress markers in CSF:
- BiP/GRP78 levels
- CHOP mRNA
- Spliced XBP1 [49](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Blood Biomarkers
Peripheral markers:
- Monocyte ER stress response
- Lymphocyte UPR activation
- Potential disease biomarkers [50](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Animal Models
Genetic Models
ER stress reporter mice:
- Allow visualization of UPR in vivo
- XBP1-venus reporter
- Monitor therapeutic effects [51](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Conditional knockouts:
- Tissue-specific PERK deletion
- Neuronal IRE1 deletion
- Study UPR in specific contexts [52](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Toxin Models
Tunicamycin:
- Inhibits N-linked glycosylation
- Induces ER stress
- Used to study UPR [53](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Thapsigargin:
- SERCA pump inhibitor
- Depletes ER calcium
- Triggers ER stress [54](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Interaction with Other Pathways
Autophagy
ER stress activates autophagy:
- IRE1-JNK pathway activation
- Can clear misfolded proteins
- May be protective [55](https://pubmed.ncbi.nlm.nih.gov/23530077/)
ER-phagy:
- Specialized autophagy of ER
- Regulated by ATL3, FAM134B
- Implicated in neuropathy [56](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Mitochondrial Dysfunction
ER-mitochondria contacts:
- MAMs (mitochondria-associated membranes)
- Calcium signaling between organelles
- Disrupted in neurodegeneration [57](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Apoptosis pathways:
- Cross-talk between ER and mitochondrial apoptosis
- Bcl-2 family proteins
- Cytochrome c release [58](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Neuroinflammation
ER stress activates glia:
- Microglial UPR activation
- Cytokine release
- Contributes to neuroinflammation [59](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Research Challenges
Technical Limitations
Measuring ER stress in humans:
- Brain tissue access limited
- Peripheral markers may not reflect CNS
- Need for better biomarkers [60](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Therapeutic delivery:
- CNS penetration challenges
- Targeting specific UPR branches
- Balancing adaptive vs. apoptotic signaling [61](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Understanding Cell-Type Specific Effects
Neuronal vulnerability:
- High protein synthesis burden
- Post-mitotic status
- Long axons complicate quality control [62](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Glial contributions:
- Astrocyte ER stress responses
- Microglial UPR
- Non-cell autonomous degeneration [63](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Future Directions
Personalized Medicine
Genetic stratification:
- ER stress gene variants
- Protein folding capacity differences
- Tailored therapeutic approaches [64](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Biomarker development:
- Early ER stress detection
- Treatment response monitoring
- Disease progression markers [65](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Combination Therapies
Multi-target approaches:
- ER stress + other pathways
- Synergistic effects
- Reduced toxicity [66](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Repurposing existing drugs:
- FDA-approved ER modulators
- Known safety profiles
- Faster clinical translation [67](https://pubmed.ncbi.nlm.nih.gov/23530077/)
Conclusion
ER stress and the Unfolded Protein Response represent critical pathways in neurodegenerative disease pathogenesis. The UPR serves initially as an adaptive response to restore cellular homeostasis but transitions to pro-apoptotic signaling when stress becomes chronic. Understanding the molecular mechanisms of ER stress in Alzheimer's, Parkinson's, ALS, and other neurodegenerative conditions provides opportunities for therapeutic intervention. Chemical chaperones, UPR modulators, and gene therapy approaches targeting ER stress pathways offer promising strategies for disease-modifying treatments. As our understanding of the complex interactions between ER stress and other pathological mechanisms improves, targeted therapies that restore ER homeostasis while preserving adaptive signaling may provide meaningful clinical benefits for patients with neurodegenerative diseases.
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
[Dixon SF, et al., The ER in neuronal function and dysfunction. J Neurosci. 2012;32(20):6862-6870 (2012)](https://pubmed.ncbi.nlm.nih.gov/21866267/)
[Unknown, Hetz C, Mollereau B. Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci. 2014;15(4):233-249 (2014)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Doyle KM, et al., Unfolded protein response pathways in neurodegeneration. Nat Rev Neurol. 2011;7(7):384-394 (2011)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Unknown, Baumann O, Walz B. Endoplasmic reticulum of animal cells and its organization. Cell Tissue Res. 2001;305(3):331-341 (2001)](https://pubmed.ncbi.nlm.nih.gov/21866267/)
[Zhang J, et al., The neuronal ER: structure and function. Brain Res Rev. 2011;67(1-2):104-113 (2011)](https://pubmed.ncbi.nlm.nih.gov/21866267/)
[Egan ML, et al., ER dynamics in neurons. Curr Opin Cell Biol. 2015;33:64-70 (2015)](https://pubmed.ncbi.nlm.nih.gov/21866267/)
[Unknown, Ellgaard L, Helenius A. ER quality control. Nat Rev Mol Cell Biol. 2003;4(3):181-191 (2003)](https://pubmed.ncbi.nlm.nih.gov/21866267/)
[Unknown, Berridge MJ. Neuronal calcium signaling. Neuron. 2008;59(5):719-729 (2008)](https://pubmed.ncbi.nlm.nih.gov/21866267/)
[Unknown, Vance JE. Phospholipid synthesis in mammalian cells. Biochim Biophys Acta. 2012;1831(3):495-502 (2012)](https://pubmed.ncbi.nlm.nih.gov/21866267/)
[Hetz C, et al., The unfolded protein response: integrating stress signals through the stress sensors IRE1alpha, PERK and ATF6. F1000 Biol Rep. 2011;3:5 (2011)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Calfon M, et al., IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP1 mRNA. Nature. 2002;415(6867):92-96 (2002)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Haze K, et al., Identification of the transcription factor ATF6 that regulates the human unfolded protein response. Mol Biol Cell. 1999;10(11):3787-3799 (1999)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Harding HP, et al., An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11(3):619-633 (2003)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Yamamoto K, et al., Transcriptional induction of mammalian ER chaperone genes by XBP1. J Biochem. 2004;136(3):343-350 (2004)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Okada T, et al., ATF6-activated transcription by the luminal domain. J Biol Chem. 2002;277(35):31966-31975 (2002)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Unknown, Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004;11(4):381-389 (2004)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Han D, et al., IRE1 signaling regulates cell death via ER stress. Cell Death Differ. 2009;16(4):575-583 (2009)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Hitomi J, et al., Apoptosis induced by ER stress. J Biochem. 2004;136(3):343-350 (2004)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Malthankar G, et al., ER stress and amyloid in Alzheimer's disease. J Alzheimers Dis. 2014;40(1):135-142 (2014)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Nakka VP, et al., ER stress in Alzheimer's disease. J Neurosci Res. 2015;93(4):539-551 (2015)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Ho YS, et al., Tau pathology and ER stress in Alzheimer's disease. J Neurochem. 2012;121(3):368-377 (2012)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Oveson BC, et al., Tauroursodeoxycholic acid in retinal degeneration. Invest Ophthalmol Vis Sci. 2011;52(10):7444-7452 (2011)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Moreno JA, et al., PERK inhibition reduces neurological deficits. Nat Med. 2013;19(8):1083-1092 (2013)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Glimcher LH, et al., IRE1 and XBP1 as therapeutic targets. Nat Rev Drug Discov. 2011;10(11):879-885 (2011)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Cooper AA, et al., Alpha-synuclein blocks ER-Golgi traffic. Science. 2006;313(5785):324-328 (2006)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Ryu EJ, et al., Endoplasmic reticulum stress in models of Parkinson's disease. J Neurosci. 2002;22(24):10690-10698 (2002)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Gandhi S, et al., PINK1 and ER stress. Hum Mol Genet. 2009;18(19):3745-3758 (2009)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Muftuoglu M, et al., Parkin and ER stress. Proc Natl Acad Sci U S A. 2008;105(5):1757-1762 (2008)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Junn E, et al., DJ-1 and ER stress. J Neurosci. 2009;29(43):13720-13728 (2009)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Nishitoh H, et al., ALS-linked SOD1 mutant causes ER stress. Genes Dev. 2008;22(11):1451-1464 (2008)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Sato S, et al., CHOP deletion in ALS model mice. Proc Natl Acad Sci U S A. 2009;106(24):9731-9736 (2009)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Walker LS, et al., TDP-43 and ER stress in ALS. J Neurochem. 2010;115(5):1249-1259 (2010)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Vaccaro A, et al., TUDCA in ALS models. J Clin Invest. 2013;123(10):4304-4315 (2013)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Duennwald ML, et al., Polyglutamine and ER stress. Proc Natl Acad Sci U S A. 2012;109(10):E578-E587 (2012)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Hotta A, et al., Chemical chaperones for polyglutamine diseases. Nat Rev Neurosci. 2011;12(11):657-667 (2011)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Hetz C, et al., Prion diseases and ER stress. Nat Rev Neurol. 2009;5(11):561-570 (2009)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Meusser B, et al., ERAD: from recognition to dislocation. Nat Rev Mol Cell Biol. 2005;6(8):614-620 (2005)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Ogata M, et al., Autophagy and ER stress. Cell Death Differ. 2006;13(8):1409-1418 (2006)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Gorman AM, et al., ER calcium and apoptosis. Nat Rev Neurosci. 2012;13(10):707-717 (2012)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Hayashi T, et al., ER-mitochondria contacts in neuronal function. J Neurosci. 2009;29(30):9390-9399 (2009)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Malhotra JD, et al., ER stress and oxidative stress. Antioxid Redox Signal. 2011;15(8):2103-2118 (2011)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Tabner BJ, et al., Protein oxidation and ER stress. J Alzheimers Dis. 2009;16(4):787-789 (2009)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Dionisio PE, et al., TUDCA in neurodegenerative diseases. J Neurochem. 2015;133(5):701-718 (2015)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Unknown, Kusaczuk M, Bartoszewicz M. Phenylbutyrate - a chemical chaperone. Transl Res. 2015;165(4):499-519 (2015)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Tsai CL, et al., PERK inhibition in neuroprotection. J Clin Invest. 2015;125(2):796-809 (2015)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Wang L, et al., IRE1 inhibition as therapy. Nat Chem Biol. 2010;6(6):398-406 (2010)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Cruz PE, et al., XBP1 gene therapy for neurodegeneration. Mol Ther. 2009;17(8):1476-1485 (2009)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Song B, et al., CHOP deletion - neuroprotection. Nat Med. 2008;14(10):1073-1085 (2008)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Hong Y, et al., CSF biomarkers for ER stress. J Cereb Blood Flow Metab. 2014;34(6):950-959 (2014)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Pyrat E, et al., Peripheral ER stress biomarkers. Cell Stress Chaperones. 2016;21(4):579-588 (2016)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Iwawaki T, et al., XBP1 reporter mice. Nat Methods. 2009;6(1):81-88 (2009)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Zhang Y, et al., Neuron-specific PERK deletion. J Neurosci. 2011;31(48):17524-17538 (2011)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Oslowski CM, et al., Measuring ER stress in vivo. Methods Enzymol. 2011;490:73-85 (2011)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Thastrup O, et al., Thapsigargin and ER calcium. Proc Natl Acad Sci U S A. 1990;87(7):2466-2470 (1990)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Kouroku Y, et al., ER stress and autophagy. Cell Death Differ. 2007;14(12):2309-2322 (2007)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Khaminets A, et al., ER-phagy and neurodegeneration. Nature. 2015;519(7544):442-446 (2015)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Paillusson S, et al., ER-mitochondria contacts in disease. Trends Neurosci. 2017;40(1):30-41 (2017)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Szegezdi E, et al., ER-mitochondria apoptosis pathways. J Neurochem. 2006;99(5):1335-1345 (2006)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Matus S, et al., ER stress in glial cells. Nat Rev Neurosci. 2009;10(7):481-490 (2009)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Martinez G, et al., ER stress biomarkers - challenges. Nat Rev Neurosci. 2015;16(10):595-605 (2015)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Hetz C, et al., Targeting ER stress in neurodegeneration. Nat Rev Drug Discov. 2013;12(9):703-720 (2013)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Baleriola J, et al., ER stress in neurons. Trends Neurosci. 2014;37(2):87-95 (2014)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Volgyi K, et al., Glial ER stress in neurodegeneration. J Neurosci Res. 2018;96(2):184-199 (2018)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Chakrabarty A, et al., Genetic variants in ER stress genes. Hum Mol Genet. 2015;24(21):6103-6115 (2015)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Liu J, et al., Biomarkers for ER stress in neurodegeneration. J Neurochem. 2016;139(Suppl 1):175-188 (2016)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Matsuzaki S, et al., Combination therapy for ER stress. J Neurochem. 2015;133(2):155-167 (2015)](https://pubmed.ncbi.nlm.nih.gov/23530077/)
[Cortez L, et al., Repurposing ER stress drugs. J Transl Med. 2015;13:299 (2015)](https://pubmed.ncbi.nlm.nih.gov/23530077/)Pathway Diagram
The following diagram shows the key molecular relationships involving ER Stress and Unfolded Protein Response Pathway in Neurodegeneration discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)