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Long-term mitochondrial stress induces early steps of Tau aggregation by increasing reactive oxygen species levels and affecting cellular proteostasis
Accumulating evidence indicates that mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases. Both of these conditions are often associated with an increase in protein aggregation. However, still unknown are the specific defects of mitochondrial biology that play a cr...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9635289/ https://www.ncbi.nlm.nih.gov/pubmed/35446108 http://dx.doi.org/10.1091/mbc.E21-11-0553 |
Sumario: | Accumulating evidence indicates that mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases. Both of these conditions are often associated with an increase in protein aggregation. However, still unknown are the specific defects of mitochondrial biology that play a critical role in the development of Alzheimer’s disease, in which Tau protein aggregates are observed in the brains of some patients. Here, we report that long-term mitochondrial stress triggered Tau dimerization, which is the first step of protein aggregation. Mitochondrial dysfunction was induced in HEK293T cells that received prolonged treatment with rotenone and in HEK293T cells with the knockout of NDUFA11 protein. To monitor changes in Tau protein aggregation, we took advantage of the bimolecular fluorescence complementation assay using HEK293T cells that were transfected with plasmids that encoded Tau. Inhibition of the ISR with ISRIB induced Tau dimerization, whereas ISR activation with salubrinal, guanabenz, and sephin1 partially reversed this process. Cells that were treated with ROS scavengers, N-acetyl-l-cysteine or MitoQ, significantly reduced the amount of ROS and Tau dimerization, indicating the involvement of oxidative stress in Tau aggregation. Our results indicate that long-term mitochondrial stress may induce early steps of Tau protein aggregation by affecting oxidative balance and cellular proteostasis. |
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