Small‑molecule PKR‑like endoplasmic reticulum kinase inhibitors as a novel targeted therapy for Parkinson's disease

Lusa, Weronika; Rozpędek‐Kamińska, Wioletta; Siwecka, Natalia; Galita, Grzegorz; Majsterek, Ireneusz; Kucharska, Ewa

doi:10.3892/mmr.2023.12989

Cited by 4 publications

(3 citation statements)

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“…Glaxo Smith Kline developed GSK2606414 (GSK414); Amgen developed AMG PERK 44; Eli Lilly developed Ly4. In our laboratory we developed specific inhibitors for PERK treatment in neurodegenerative disorders including glaucoma (termed PERKi) [33][34][35][36]. The intricacies of the transcription and translation program controlled by PERK invites research into different tissue types and into combinations with other drugs to assess its role as an efficacious therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling to Unfolded Proteins Response as a Risk Modulator of Patients with Rheumatoid Arthritis

Kucharska-Lusina,

Skrzypek,

Binda

et al. 2024

IJMS

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Rheumatoid arthritis (RA) is a chronic inflammatory disease. Despite new methods of diagnostics and treatment as well as extensive biological and immunosuppressive treatment, the etiology of RA is not fully understood. Moreover, the problem of diagnosis and treatment of RA patients is still current and affects a large group of patients. It is suggested that endoplasmic reticulum (ER)-related features may impair adaptation to chronic stress, inferring the risk of rheumatoid arthritis. The main goal in this study was evaluation of changes in mRNA translation to determine chronic ER stress conditions in rheumatoid arthritis patients. The study group consist of 86 individuals including a total of 56 rheumatoid arthritis patients and 30 healthy controls. The expression level of mRNA form blood samples of RA patients as well as controls of the unfolded protein response (UPR)-associated genes (p-eIF2, BCL-2, PERK, ATF4, and BAX) were investigated using real-time qPCR. GAPDH expression was used as a standard control. Considering the median, the expression levels of PERK, BCL-2, p-eIF2, ATF4, and BAX were found to be significantly increased in the blood of RA patients compared with the control group. The p-value for the PERK gene was 0.0000000036, the p-value for the BCL-2 gene was 0.000000014, the p-value for the p-eIF2 gene was 0.006948, the p-value for the ATF4 gene was 0.0000056, and the p-value for the BAX gene was 0.00019, respectively. Thus, it can be concluded that the targeting of the components of the PERK-dependent UPR signaling pathway via small-molecule PERK inhibitors may contribute to the development of novel, innovative treatment strategies against rheumatoid arthritis.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling to Unfolded Proteins Response as a Risk Modulator of Patients with Rheumatoid Arthritis

Kucharska-Lusina,

Skrzypek,

Binda

et al. 2024

IJMS

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“…LDN-87357 is a highly specific PERK inhibitor selected in HTS, which is expected to cross the BBB. The compound rescued neurodegeneration in a cellular model of PD, and it could provide a promising alternative to GSK inhibitors [ 286 ]. It needs, however, in vivo testing to assess if pancreatic toxicity was particularly attributed to GSK or if this is a general side effect of PERK inhibitors.…”

Section: Drugs Targeting α-Synucleinmentioning

confidence: 99%

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

Siwecka,

Saramowicz,

Galita

et al. 2023

Pharmaceutics

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α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a frequent cause of neurodegeneration. The most common α-synucleinopathy, Parkinson’s disease (PD), is caused by abnormal accumulation of α-syn in the dopaminergic neurons of the midbrain. This results in protein overload, activation of endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis and neurodegeneration. To date, the available treatment options for PD are only symptomatic and rely on dopamine replacement therapy or palliative surgery. As the prevalence of PD has skyrocketed in recent years, there is a pending issue for development of new disease-modifying strategies. These include anti-aggregative agents that target α-syn directly (gene therapy, small molecules and immunization), indirectly (modulators of ER stress, oxidative stress and clearance pathways) or combine both actions (natural compounds). Herein, we provide an overview on the characteristic features of the structure and pathogenic mechanisms of α-syn that could be targeted with novel molecular-based therapies.

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“…In addition, GSK2606414 could increase dopamine levels, restore the synaptic proteins, and improve motor deficits in mice (Mercado et al, 2018). Small-molecule PERK inhibitor LDN-87357 successfully reduced mRNA levels of ER stress markers and caspase3-associated apoptosis in SH-SY5Y cell PD model (Lusa et al, 2023). On the other hand, to regulate the UPR branch, Boyce et al discovered a "different way" of the lowtoxicity compound Salubrinal (Boyce et al, 2005).…”

Section: Perk/eif2α/atf4 Pathwaymentioning

confidence: 99%

Strategies targeting endoplasmic reticulum stress to improve Parkinson’s disease

Wang,

Qu,

Zhang

et al. 2023

Front. Pharmacol.

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Parkinson’s disease (PD) is a common neurodegenerative disorder with motor symptoms, which is caused by the progressive death of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring in the SNpc DA neurons is an early event in the development of PD. ER stress triggers the activation of unfolded protein response (UPR) to reduce stress and restore ER function. However, excessive and continuous ER stress and UPR exacerbate the risk of DA neuron death through crosstalk with other PD events. Thus, ER stress is considered a promising therapeutic target for the treatment of PD. Various strategies targeting ER stress through the modulation of UPR signaling, the increase of ER’s protein folding ability, and the enhancement of protein degradation are developed to alleviate neuronal death in PD models. In this review, we summarize the pathological role of ER stress in PD and update the strategies targeting ER stress to improve ER protein homeostasis and PD-related events.

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Small‑molecule PKR‑like endoplasmic reticulum kinase inhibitors as a novel targeted therapy for Parkinson's disease

Cited by 4 publications

References 0 publications

Gene Expression Profiling to Unfolded Proteins Response as a Risk Modulator of Patients with Rheumatoid Arthritis

Gene Expression Profiling to Unfolded Proteins Response as a Risk Modulator of Patients with Rheumatoid Arthritis

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

Strategies targeting endoplasmic reticulum stress to improve Parkinson’s disease

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