The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases
Open accessAbstract
Higher prevalence of neurodegenerative diseases is strictly connected with progressive aging of the world population. Interestingly, a broad range of age-related, neurodegenerative diseases is characterized by a common pathological mechanism—accumulation of misfolded and unfolded proteins within the cells. Under certain circumstances, such protein aggregates may evoke endoplasmic reticulum (ER) stress conditions and subsequent activation of the unfolded protein response (UPR) signaling pathways via the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent manner. Under mild to moderate ER stress, UPR has a pro-adaptive role. However, severe or long-termed ER stress conditions directly evoke shift of the UPR toward its pro-apoptotic branch, which is considered to be a possible cause of neurodegeneration. To this day, there is no effective cure for Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), or prion disease. Currently available treatment approaches for these diseases are only symptomatic and cannot affect the disease progression. Treatment strategies, currently under detailed research, include inhibition of the PERK-dependent UPR signaling branches. The newest data have reported that the use of small-molecule inhibitors of the PERK-mediated signaling branches may contribute to the development of a novel, ground-breaking therapeutic approach for neurodegeneration. In this review, we critically describe all the aspects associated with such targeted therapy against neurodegenerative proteopathies.
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Oral administration of highly selective PERK inhibitors significantly reduces neurodegeneration and clinical disease in prion-infected mice, crossing the BBB efficiently.
“In fact, the oral administration of highly selective PERK inhibitors significantly reduces neurodegeneration and clinical disease in prion-infected mice, crossing the BBB efficiently [402,403].”
From GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review (2022) · cites this paper as [403]
Section 6.1 describes GSK2606414 as highly selective and reports a neuroprotective effect in prion-infected mice. It describes oral treatment and improved clinical symptoms in a different mouse model, but does not state that the prion-infected mice received it orally, document their clinical improvement, or say that the inhibitor efficiently crossed the blood–brain barrier. The References list a prion study with oral treatment and prevention of clinical disease in its title, but the review’s discussion does not substantiate all the details attributed here. (LLM, conf=0.85)
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References 312 · Cited by 84
Research works printed but not linked: 1
- [286]Li J.L. Trazodone The Essence of Analgesia and Analgesics Cambridge University Press Cambridge, UK 2010 351 353 9780511841378
- Authors
- Rozpędek-Kamińska, W., Siwecka, N., Wawrzynkiewicz, A., Wojtczak, R., Pytel, D., Diehl, J. A., & Majsterek, I.
- Affiliations
- Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, 90-419 Lodz, Poland
- Medical University of Lodz (PL)
- Medical University of South Carolina (US)
- Corresponding author
- Majsterek, Ireneusz
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2020-03-19
- Volume
- 21
- Issue
- 6
- Pages
- 2108
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC7139310
- OpenAlex
- W3012180584
- Cited by
- 84
- References
- 312
- Citations by year
- 2026: 6 · 2025: 19 · 2024: 11 · 2023: 14 · 2022: 14 · 2021: 13 · 2020: 5 · 2019: 2
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Narodowe Centrum Nauki (2015/19/N/NZ3/00055, 2016/21/B/NZ5/01411, 2013/10/M/NZ1/00280)
- Uniwersytet Medyczny w Lodzi (502-03/5-108-05/502-54-224-18, 564/5-000-00/564-20-035, 564/5-000-00/564-20-038)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- PERK, unfolded protein response, endoplasmic reticulum stress, neurodegenerative diseases, protein aggregation, misfolded proteins, PERK inhibitor, small molecule inhibitors, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, proteinopathies, apoptosis
- MeSH terms
- Alzheimer Disease, Animals, Humans, Neurodegenerative Diseases, eIF-2 Kinase, Protein Kinase Inhibitors, Small Molecule Libraries, Unfolded Protein Response, Molecular Targeted Therapy, Endoplasmic Reticulum Stress
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