The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases.

The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases.

Publication date: Mar 19, 2020

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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Rozpedek-Kami’nska, W., Siwecka, N., Wawrzynkiewicz, A., Wojtczak, R., Pytel, D., Diehl, J.A., and , Majsterek. The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases. 24458. 2020 Int J Mol Sci (21):6.

Concepts Keywords
Aging Population GSK2606414
Alzheimer Apoptosis
Apoptotic Neurodegeneration
Endoplasmic Reticulum Endoplasmic reticulum
ER Stress PERK inhibitors
Huntington Unfolded protein response
Kinase Branches of biology
Neurodegeneration Related neurodegenerative diseases
Neurodegenerative
Neurodegenerative Diseases
Parkinson
Prion Disease
Progressive
Proteopathies
RNA
Sci
Small Molecule
Stress
Targeted Therapy

Semantics

Type Source Name
disease MESH Neurodegenerative Diseases
pathway REACTOME Neurodegenerative Diseases
disease MESH aging
disease MESH prion disease
disease MESH disease progression
disease MESH development
pathway KEGG Apoptosis
disease MESH endoplasmic reticulum stress

Original Article

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