Abstract
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.
Highlights
Neurodegeneration is generally defined as progressive, irreversible loss of neurons, which may affect either the peripheral or central nervous system (CNS)
The molecular mechanism that evokes shift of the unfolded protein response (UPR) from pro-adaptive toward pro-apoptotic still remains unclear, there is a plethora of studies that have demonstrated that inhibition of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent UPR signaling pathways may constitute a novel, ground-breaking treatment strategy against neurodegenerative diseases
The results of studies on neurodegeneration that required the use of GSK inhibitors may be irrelevant, as it has been proven that both inhibitors are more prone to inhibit the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-dependent apoptotic pathway rather than PERK
Summary
Neurodegeneration is generally defined as progressive, irreversible loss of neurons, which may affect either the peripheral or central nervous system (CNS). A study by Elharram et al has demonstrated that, in an oxidative stress-dependent mouse model of age-related cognitive impairment with AD-like biochemical and structural pathologies with deletion of the aldehyde dehydrogenease 2 gene (Aldh2-/-), treatment with D-PUFAs for 18 weeks evoked an approximate 55% decrease of F2-isoprostanes (F2-IsoPs) and 20–25% decrease of prostaglandin F2α (PGF2α) in both the cortex and hippocampus, as compared to H-PUFA-treated Aldh2-/- mice for 18 weeks. This aforementioned study indicated that D-PUFAs significantly reduce LPO brain products in an Aldh2-/- mouse model of sporadic AD. Inhibition of the PERK-mediated, pro-apoptotic UPR signaling branches on the molecular level may contribute to the development of a novel, targeted treatment strategy against neurodegeneration [14]
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