Protein Misfolding and Aggregation as a Mechanistic Link Between Chronic Pain and Neurodegenerative Diseases
Abstract
:1. Introduction
2. Materials and Methods
3. Protein Misfolding and Aggregation: Molecular Mechanisms
3.1. Protein Folding and Molecular Chaperones
3.2. Proteostasis and Protein Quality Control System
3.3. Unfolded Protein Response (UPR) and ER Stress
3.4. Key Disease-Associated Proteins and Prion-like Propagation
3.5. Neuroinflammation and Oxidative Stress in Protein Misfolding
4. Chronic Pain and Protein Misfolding: Mechanistic Insights
4.1. Evidence of Protein Aggregation in Chronic Pain Conditions
4.2. Proteostasis Dysfunction and Neuronal Stress in Chronic Pain
4.3. Chronic Pain as a Risk Factor for Protein Misfolding
5. Neurodegeneration and Chronic Pain: Common Pathways
5.1. Shared Neuroinflammatory and Neuroimmune Mechanisms
5.2. Dysregulation of Protein Homeostasis in Pain and NDs
5.3. Prion-like Propagation of Protein Aggregates in Pain and NDs
5.4. Impact of Chronic Pain on Neurodegenerative Progression
6. Potential Therapeutic Implications
6.1. Chaperone Inhibitors
6.2. Modulation of Autophagy and Proteasomal Degradation
6.3. Glial Inhibitors
6.4. Antioxidant Therapy
6.5. Future Directions
7. Conclusions
Author Contributions
Funding
Informed Consent Statement
Conflicts of Interest
References
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Author | Year | Drug/Target | Mechanism of Action | Preclinical/Clinical Evidence | Challenges and Future Directions |
---|---|---|---|---|---|
Jiang et al. [193] | 2017 | N-acetylcysteine | Restores glutathione, modulates HSPs, protects against proteasome inhibitor toxicity | Preclinical (neuroblastoma cell model) | Requires clinical trials in pain conditions |
Gao et al. [194] | 2019 | Aspirin | Inhibits proteasomal degradation, promotes aggregate clearance via K63 ubiquitination | Preclinical (PD mouse model) | Repurposing needs validation; risk of systemic effects |
Kan et al. [37] | 2024 | PKCε inhibitor | Reduces ER stress and autophagy activation | Preclinical (diabetic neuropathy model) | Needs human translation |
Krukowski et al. [195] | 2017 | PFM-µ (Hsp70/Hsp90 inhibitor) | Inhibits chaperone activity and p53, prevents mitochondrial p53 aggregation | Preclinical (chemotherapy-induced neuropathy models) | No clinical trials |
Stine et al. [196] | 2019 | Hsp90 inhibitors | Block opioid-induced analgesia via TLR4 modulation | Preclinical (mouse models of bone pain) | Mixed effects; may impair pain relief from opioids |
Tikka et al. [197] | 2001 | Minocycline | Inhibits microglial activation and inflammatory cytokine production | Preclinical (primary neuronal cultures model) | Requires exploration in chronic pain with misfolding |
Lisi et al. [198] | 2012 | Rapamycin (mTOR inhibitor) | Enhances autophagy, reduces inflammation | Preclinical (autoimmune encephalitis model) | Immunosuppression risk; unclear dosing for pain relief |
Kraft et al. [199] | 2021 | Trehalose | Activates TFEB to enhance autophagy, clears protein aggregates | Preclinical (mice spared nerve injury model) | Sedation reported; require further safety and efficacy studies |
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Brezic, N.; Gligorevic, S.; Sic, A.; Knezevic, N.N. Protein Misfolding and Aggregation as a Mechanistic Link Between Chronic Pain and Neurodegenerative Diseases. Curr. Issues Mol. Biol. 2025, 47, 259. https://doi.org/10.3390/cimb47040259
Brezic N, Gligorevic S, Sic A, Knezevic NN. Protein Misfolding and Aggregation as a Mechanistic Link Between Chronic Pain and Neurodegenerative Diseases. Current Issues in Molecular Biology. 2025; 47(4):259. https://doi.org/10.3390/cimb47040259
Chicago/Turabian StyleBrezic, Nebojsa, Strahinja Gligorevic, Aleksandar Sic, and Nebojsa Nick Knezevic. 2025. "Protein Misfolding and Aggregation as a Mechanistic Link Between Chronic Pain and Neurodegenerative Diseases" Current Issues in Molecular Biology 47, no. 4: 259. https://doi.org/10.3390/cimb47040259
APA StyleBrezic, N., Gligorevic, S., Sic, A., & Knezevic, N. N. (2025). Protein Misfolding and Aggregation as a Mechanistic Link Between Chronic Pain and Neurodegenerative Diseases. Current Issues in Molecular Biology, 47(4), 259. https://doi.org/10.3390/cimb47040259