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Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two incurable neurodegenerative diseases that exist on a clinical, genetic and pathological spectrum. The VCP gene is highly relevant, being directly implicated in both FTD and ALS. Here, we investigate the effects of VCP mutations on the cellular homoeostasis of human induced pluripotent stem cell-derived cortical neurons, focusing on endolysosomal biology and tau pathology. We found that VCP mutations cause abnormal accumulation of enlarged endolysosomes accompanied by impaired interaction between two nuclear RNA binding proteins: fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) in human cortical neurons. The spatial dissociation of intranuclear FUS and SFPQ correlates with alternative splicing of the MAPT pre-mRNA and increased tau phosphorylation. Importantly, we show that inducing 4R tau expression using antisense oligonucleotide technology is sufficient to drive neurodegeneration in control human neurons, which phenocopies VCP -mutant neurons. In summary, our findings demonstrate that tau hyperphosphorylation, endolysosomal dysfunction, lysosomal membrane rupture, endoplasmic reticulum stress and apoptosis are driven by a pathogenic increase in 4R tau. [ABSTRACT FROM AUTHOR]

Hypoxia has been reported to be a critical microenvironmental factor that induces cancer metastasis and proliferation in gastric, liver and hepatic cancers; however, the underlying mechanisms of this are largely unknown. Long noncoding RNAs (lncRNAs) have emerged as crucial factors of several aspects of tumor malignancy, including tumorigenesis, metastasis and chemoresistance. However, the potential association of lncRNAs with hypoxia-induced cancer malignancy remains to be determined. In the present study, the differential expression of lncRNAs following the induction of hypoxia in A549 lung adenocarcinoma cells was analyzed reverse transcription-quantitative polymerase chain reaction. It was identified that the lncRNA metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) was upregulated significantly by hypoxia in A549 cells. By considering its promotive effects on malignant tumor behaviors, in the present study, it was identified that upregulated MALAT-1 released the binding of PTB-associated splicing factor (PSF) to its target gene, GAGE6, and thus promoted proliferation, migration and invasion of A549 cells following hypoxia exposure. These results advance the overall understanding of the mechanism of hypoxia-induced lung cancer metastasis and may assist in the development of novel therapeutics. [ABSTRACT FROM AUTHOR]