bims-ershed 2023-04-02 papers

Mol Med Rep. 2023 May;pii: 102. [Epub ahead of print]27(5):

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

Weronika Lusa, Wioletta Rozpędek-Kamińska, Natalia Siwecka, Grzegorz Galita, Ireneusz Majsterek, Ewa Kucharska.

Parkinson's disease (PD) is the second most common neurodegenerative disorder in worldwide and remains a therapeutic challenge due to the low efficacy of current treatments. Numerous studies have demonstrated the pivotal role of endoplasmic reticulum (ER) stress in PD pathogenesis. ER stress, followed by activation of the protein kinase RNA‑like endoplasmic reticulum kinase (PERK)‑dependent branch of the unfolded protein response signaling pathway, ultimately leads to neural cell death and dopaminergic neurodegeneration in PD. Therefore, the present study evaluated the effectiveness of the small‑molecule PERK inhibitor LDN‑87357 in an in vitro PD model using the human neuroblastoma SH‑SY5Y cell line. To assess the mRNA expression levels of the pro‑apoptotic ER stress markers, the TaqMan Gene Expression Assay was performed. Cytotoxicity was assessed using a colorimetric 2,3‑bis‑(2‑methoxy‑4‑nitro‑5‑sulfophenyl)‑ 2H‑tetrazolium‑5‑carboxanilide assay and apoptosis was assessed using a caspase‑3 assay. Moreover, cell cycle progression was evaluated using flow cytometry. The results indicated that LDN‑87357 treatment induced a significant decrease in ER stress markers gene expression in SH‑SY5Y cells exposed to ER stress. Furthermore, LDN‑87357 significantly increased viability, diminished apoptosis and restored the normal cell cycle distribution of SH‑SY5Y cells after ER stress induction. Therefore, the evaluation of small‑molecule PERK inhibitors, such as LDN‑87357, may lead to the development of novel therapeutic strategies against PD.

Keywords: Parkinson's disease; Parkinson's disease treatment; apoptosis; endoplasmic reticulum stress; neurodegeneration; protein kinase RNA‑like endoplasmic reticulum kinase; small‑molecule PERK inhibitor; unfolded protein response

DOI: https://doi.org/10.3892/mmr.2023.12989

Front Pharmacol. 2023 ;14 1176805

Editorial: Restoring endoplasmic reticulum proteostasis to treat neurological disorders.

Danilo B Medinas, Najla Arshad, Sonam Parakh, Sayuri Miyamoto, Vanessa Olzon Zambelli.

Keywords: drug discovery; endoplasmic reticulum; ischemia-reperfusion injury; neurological disorders; proteostasis; small molecules; spinal cord injury; unfolded protein response

DOI: https://doi.org/10.3389/fphar.2023.1176805

Front Cell Dev Biol. 2023 ;11 1086964

The dark side of mRNA translation and the translation machinery in glioblastoma.

Angélica Montiel-Dávalos, Yeniffer Ayala, Greco Hernández.

Among the different types of cancer affecting the central nervous system (CNS), glioblastoma (GB) is classified by the World Health Organization (WHO) as the most common and aggressive CNS cancer in adults. GB incidence is more frequent among persons aged 45-55 years old. GB treatments are based on tumor resection, radiation, and chemotherapies. The current development of novel molecular biomarkers (MB) has led to a more accurate prediction of GB progression. Moreover, clinical, epidemiological, and experimental studies have established genetic variants consistently associated with the risk of suffering GB. However, despite the advances in these fields, the survival expectancy of GB patients is still shorter than 2 years. Thus, fundamental processes inducing tumor onset and progression remain to be elucidated. In recent years, mRNA translation has been in the spotlight, as its dysregulation is emerging as a key cause of GB. In particular, the initiation phase of translation is most involved in this process. Among the crucial events, the machinery performing this phase undergoes a reconfiguration under the hypoxic conditions in the tumor microenvironment. In addition, ribosomal proteins (RPs) have been reported to play translation-independent roles in GB development. This review focuses on the research elucidating the tight relationship between translation initiation, the translation machinery, and GB. We also summarize the state-of-the-art drugs targeting the translation machinery to improve patients' survival. Overall, the recent advances in this field are shedding new light on the dark side of translation in GB.

Keywords: TMZ (temozolomide); cancer; eIF4E; glioblastoma; ribosomal proteins (RP); translation initiation; translation machinery

DOI: https://doi.org/10.3389/fcell.2023.1086964

Biomedicines. 2023 Feb 27. pii: 722. [Epub ahead of print]11(3):

Nonsense-Mediated mRNA Decay Factor Functions in Human Health and Disease.

Lingling Sun, Justine Mailliot, Christiane Schaffitzel.

Nonsense-mediated mRNA decay (NMD) is a cellular surveillance mechanism that degrades mRNAs with a premature stop codon, avoiding the synthesis of C-terminally truncated proteins. In addition to faulty mRNAs, NMD recognises ~10% of endogenous transcripts in human cells and downregulates their expression. The up-frameshift proteins are core NMD factors and are conserved from yeast to human in structure and function. In mammals, NMD diversified into different pathways that target different mRNAs employing additional NMD factors. Here, we review our current understanding of molecular mechanisms and cellular roles of NMD pathways and the involvement of more specialised NMD factors. We describe the consequences of mutations in NMD factors leading to neurodevelopmental diseases, and the role of NMD in cancer. We highlight strategies of RNA viruses to evade recognition and decay by the NMD machinery.

Keywords: cancer; exon-junction complex; neurodevelopmental disease; nonsense-mediated mRNA decay; up-frameshift proteins; viral NMD evasion

DOI: https://doi.org/10.3390/biomedicines11030722