Endoplasmic Reticulum Stress Mechanisms in Neurodegenerative Diseases

Endoplasmic reticulum (ER) stress arises when the folding capacity of the ER is overwhelmed by misfolded or aggregated proteins or by disturbances in calcium homeostasis. In response, cells activate the unfolded protein response (UPR), a coordinated signalling network mediated by IRE1α, PERK and ATF6 transducers. While acute UPR activation aims to restore proteostasis, chronic or non-canonical ER stress can trigger apoptotic pathways, contribute to neuroinflammation and exacerbate neuronal loss. In Alzheimer’s, Parkinson’s and other neurodegenerative diseases, ER stress intersects with mitochondrial dysfunction, autophagy and altered metabolic signalling, driving synaptic failure and cognitive decline. Understanding these interconnected mechanisms offers routes to novel therapies that bolster adaptive stress responses, limit inflammatory cascades and preserve neuronal integrity.

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Endoplasmic Reticulum Stress Mechanisms in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in endoplasmic reticulum stress mechanisms in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Endoplasmic reticulum stress (ER stress): Condition arising from accumulation of misfolded proteins or perturbations in calcium homeostasis within the ER, leading to activation of cellular stress pathways.

Unfolded protein response (UPR): Integrated signalling cascade triggered by ER stress to restore proteostasis via translational attenuation, chaperone induction and, if necessary, initiation of apoptosis.

IRE1α: ER-resident kinase and endoribonuclease that initiates one branch of the UPR by splicing XBP1 mRNA and activating downstream stress responses.

PERK: ER-bound kinase that phosphorylates eIF2α to reduce global protein synthesis while selectively promoting expression of stress-adaptive genes.

ATF6: ER stress-activated transcription factor that relocates to the Golgi and nucleus to upregulate genes encoding chaperones and folding enzymes.

ER-phagy: Selective autophagic removal of ER fragments to alleviate proteostatic stress and maintain organelle integrity during prolonged ER stress.

Calcium dyshomeostasis: Disruption of calcium balance between the ER and cytosol, which can provoke ER stress and contribute to neurodegenerative signalling.

References

1. Exosomes Derived from M2 Microglial Cells Modulated by 1070‐nm Light Improve Cognition in an Alzheimer's Disease Mouse Model. Advanced Science (2023).
2. The endoplasmic reticulum stress and unfolded protein response in Alzheimer’s disease: A calcium dyshomeostasis perspective. Ageing Research Reviews (2023).
3. Adaptive responses of neuronal cells to chronic endoplasmic reticulum (ER) stress. Redox Biology (2023).