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• W2898981465 abstract "Recent reports in pathophysiology of neurodegenerative diseases (ND) have linked nuclear lamina degradation/deficits to neuronal cell death. Lamin-B1 damage is specifically involved in this process leading to nuclear envelope invagination and heterochromatin rearrangement. The underlying mechanisms involved in these events are not yet defined. In this study, while examining the effect of Thioredoxin-1(Trx1) inhibition on cell death in a model of oxidative stress, we noted robust nuclear invagination in SH-SY5Y cells. Evaluation of nuclear lamina proteins revealed lamin-B1 cleavage that was prevented by caspase-6 (CASP6) inhibitor and exacerbated after pharmacologic/genetic inhibition of Trx1 system, but not after glutathione depletion. Activation of CASP6 was upstream of CASP3/7 activation and its inhibition was sufficient to prevent cell death in our system. The effect of Trx1 redox status on CASP6 activation was assessed by administration of reduced/oxidized forms in cell-free nuclei preparation and purified enzymatic assays. Although reduced Trx1 decreased CASP6 enzymatic activity and lamin-B1 cleavage, the fully oxidized Trx1 showed opposite effects. The enhanced CASP6 activation was also associated with lower levels of DJ-1, a neuroprotective and master regulator of cellular antioxidants. The implication of our findings in ND pathophysiology was strengthened with detection of lower Trx1 levels in the hippocampi tissue of a mouse model of Alzheimer's disease. This coincided with higher CASP6 activation resulting in increased lamin-B1 and DJ-1 depletion. This study provides a first mechanistic explanation for the key regulatory role of Trx1 as a gatekeeper in activation of CASP6 and induction of nuclear invagination, an important player in ND pathophysiology." @default.
• W2898981465 created "2018-11-09" @default.
• W2898981465 creator A5001982850 @default.
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• W2898981465 date "2019-04-01" @default.
• W2898981465 modified "2023-10-17" @default.
• W2898981465 title "Thioredoxin system as a gatekeeper in caspase-6 activation and nuclear lamina integrity: Implications for Alzheimer's disease" @default.
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• W2898981465 doi "https://doi.org/10.1016/j.freeradbiomed.2019.02.010" @default.
• W2898981465 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30769159" @default.
• W2898981465 hasPublicationYear "2019" @default.
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