A fine balance between Prpf19 and Exoc7 in achieving degradation of aggregated protein and suppression of cell death in spinocerebellar ataxia type 3

Chen, Zhefan Stephen; Huang, Xiaoying; Talbot, Kevin; Chan, Ho Yin Edwin

doi:10.1038/s41419-021-03444-x

Cited by 11 publications

(7 citation statements)

References 59 publications

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“…Indeed, proteinaceous assemblies such as amyloids and prions were initially discovered in neurodegenerative diseases and were quickly attributed to an anomalous state of otherwise properly folded proteins. Many pathologies are related to a defect in protein folding and the ensuing aggregation of partially folded intermediates, including Alzheimer’s [ 7 ], Parkinson’s [ 8 ], and Huntington’s disease [ 9 ], amyotrophic lateral sclerosis [ 10 ], transmissible spongiform encephalopathies like Creutzfeldt-Jakob disease [ 11 ] and scrapies [ 12 ], and spinocerebellar ataxia [ 13 ]. The cytotoxicity of protein aggregation has also been identified at the root of the evolutionary tree, and bacterial susceptibility to protein misfolding has been proposed as the target of future antibiotics [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures

et al. 2022

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Background By 2016, signs of emergence of Plasmodium falciparum resistance to artemisinin and partner drugs were detected in the Greater Mekong Subregion. Recently, the independent evolution of artemisinin resistance has also been reported in Africa and South America. This alarming scenario calls for the urgent development of new antimalarials with novel modes of action. We investigated the interference with protein aggregation, which is potentially toxic for the cell and occurs abundantly in all Plasmodium stages, as a hitherto unexplored drug target in the pathogen. Results Attempts to exacerbate the P. falciparum proteome’s propensity to aggregation by delivering endogenous aggregative peptides to in vitro cultures of this parasite did not significantly affect their growth. In contrast, protein aggregation inhibitors clearly reduced the pathogen’s viability. One such compound, the bis(styrylpyridinium) salt YAT2150, exhibited potent antiplasmodial activity with an in vitro IC50 of 90 nM for chloroquine- and artemisinin-resistant lines, arresting asexual blood parasites at the trophozoite stage, as well as interfering with the development of both sexual and hepatic forms of Plasmodium. At its IC50, this compound is a powerful inhibitor of the aggregation of the model amyloid β peptide fragment 1-40, and it reduces the amount of aggregated proteins in P. falciparum cultures, suggesting that the underlying antimalarial mechanism consists in a generalized impairment of proteostasis in the pathogen. YAT2150 has an easy, rapid, and inexpensive synthesis, and because it fluoresces when it accumulates in its main localization in the Plasmodium cytosol, it is a theranostic agent. Conclusions Inhibiting protein aggregation in Plasmodium significantly reduces the parasite’s viability in vitro. Since YAT2150 belongs to a novel structural class of antiplasmodials with a mode of action that potentially targets multiple gene products, rapid evolution of resistance to this drug is unlikely to occur, making it a promising compound for the post-artemisinin era.

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Section: Introductionmentioning

confidence: 99%

The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures

et al. 2022

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“…Notably, biological processes that might be regulated by the sponge activity of circRNAs are particularly relevant for ALS pathology. For instance, circSLC8A1 shows four binding sites for miR-335-3p and three for miR-27a-3p, miR-27b-3p and miR-30d-3p, and the mRNA targets of these miRNAs are involved in processes that are altered in ALS such as: neuroprotection (e.g., ADAM12 [ 64 ]), DNA damage repair (e.g., HLTF [ 65 , 66 ]), protein trafficking regulation and axonal guidance/elongation (e.g., SNX18 and DPYSL3 [ 67 , 68 ]), splicing regulation (e.g., EXOC7 and FUBP1 [ 69 , 70 ]), neuronal excitability and synaptic transmission (e.g., NEDD4L [ 71 ]). Remarkably, binding sites for miR-335-3p have been found both in circSLC8A1 and in circDLC1, and all circRNAs, by sponging different miRNAs, act on genes that have a common molecular function or that are involved in the same processes.…”

Section: Resultsmentioning

confidence: 99%

FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation

Colantoni

Capauto

Alfano

et al. 2023

IJMS

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Deregulation of RNA metabolism has emerged as one of the key events leading to the degeneration of motor neurons (MNs) in Amyotrophic Lateral Sclerosis (ALS) disease. Indeed, mutations on RNA-binding proteins (RBPs) or on proteins involved in aspects of RNA metabolism account for the majority of familiar forms of ALS. In particular, the impact of the ALS-linked mutations of the RBP FUS on many aspects of RNA-related processes has been vastly investigated. FUS plays a pivotal role in splicing regulation and its mutations severely alter the exon composition of transcripts coding for proteins involved in neurogenesis, axon guidance, and synaptic activity. In this study, by using in vitro-derived human MNs, we investigate the effect of the P525L FUS mutation on non-canonical splicing events that leads to the formation of circular RNAs (circRNAs). We observed altered levels of circRNAs in FUSP525L MNs and a preferential binding of the mutant protein to introns flanking downregulated circRNAs and containing inverted Alu repeats. For a subset of circRNAs, FUSP525L also impacts their nuclear/cytoplasmic partitioning, confirming its involvement in different processes of RNA metabolism. Finally, we assess the potential of cytoplasmic circRNAs to act as miRNA sponges, with possible implications in ALS pathogenesis.

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“…As another Ubiquitin-protein ligase, pre-mRNA processing factor 19 (Prpf19/prp19) mainly involved pre-mRNA splicing and plays a neuroprotective role in the DDR. PRPF19 was upregulated during neurodegeneration, for it can antagonize exocyst complex component 7 (Exoc7) to improve neurodegeneration by degrading misfolded proteins in neurons through the ubiquitin-proteasome system, therefore, patients with MCI are often accompanied by higher PRPF19 levels than patients with normal cognitive function (Chen et al, 2021). SRC is a tyrosineprotein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase.…”

Section: A B Figure 10mentioning

confidence: 99%

Identification and validation of biomarkers based on cellular senescence in mild cognitive impairment

S.K.

Xia

Wang

et al. 2023

Front. Aging Neurosci.

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BackgroundMild cognitive impairment (MCI), a syndrome defined as decline of cognitive function greater than expected for an individual’s age and education level, occurs in up to 22.7% of elderly patients in United States, causing the heavy psychological and economic burdens to families and society. Cellular senescence (CS) is a stress response that accompanies permanent cell-cycle arrest, which has been reported to be a fundamental pathological mechanism of many age-related diseases. This study aims to explore biomarkers and potential therapeutic targets in MCI based on CS.MethodsThe mRNA expression profiles of peripheral blood samples from patients in MCI and non-MCI group were download from gene expression omnibus (GEO) database (GSE63060 for training and GSE18309 for external validation), CS-related genes were obtained from CellAge database. Weighted gene co-expression network analysis (WGCNA) was conducted to discover the key relationships behind the co-expression modules. The differentially expressed CS-related genes would be obtained through overlapping among the above datasets. Then, pathway and GO enrichment analyses were performed to further elucidate the mechanism of MCI. The protein–protein interaction network was used to extract hub genes and the logistic regression was performed to distinguish the MCI patients from controls. The hub gene-drug network, hub gene-miRNA network as well as transcription factor-gene regulatory network were used to analyze potential therapeutic targets for MCI.ResultsEight CS-related genes were identified as key gene signatures in MCI group, which were mainly enriched in the regulation of response to DNA damage stimulus, Sin3 complex and transcription corepressor activity. The receiver operating characteristic curves of logistic regression diagnostic model were constructed and presented great diagnostic value in both training and validation set.ConclusionEight CS-related hub genes – SMARCA4, GAPDH, SMARCB1, RUNX1, SRC, TRIM28, TXN, and PRPF19 – serve as candidate biomarkers for MCI and display the excellent diagnostic value. Furthermore, we also provide a theoretical basis for targeted therapy against MCI through the above hub genes.

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A fine balance between Prpf19 and Exoc7 in achieving degradation of aggregated protein and suppression of cell death in spinocerebellar ataxia type 3

Cited by 11 publications

References 59 publications

The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures

The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures

FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation

Identification and validation of biomarkers based on cellular senescence in mild cognitive impairment

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