期刊
CURRENT BIOLOGY
卷 26, 期 22, 页码 3014-3025出版社
CELL PRESS
DOI: 10.1016/j.cub.2016.09.024
关键词
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资金
- American Federation for Aging Research
- Larry L. Hillblom Foundation
- Griswold Family Fund
- Buck Institute Impact Circle
- NIH [T32 AG000266, R01 AG038688, R01 AG038012, R01 AG045835, R01 AG048072]
- NIH Office of Research Infrastructure Programs [P40 OD010440]
Reactive alpha-dicarbonyls (alpha-DCs), like methylglyoxal (MGO), accumulate with age and have been implicated in aging and various age-associated pathologies, such as diabetic complications and neurodegenerative disorders like Alzheimer's and Parkinson's diseases. Evolutionarily conserved glyoxalases are responsible for alpha-DC detoxification; however, their core biochemical regulation has remained unclear. We have established a Caenorhabditis elegans model, based on an impaired glyoxalase (glod-4/GLO1), to broadly study alpha-DC-related stress. We show that, in comparison to wild-type (N2, Bristol), glod-4 animals rapidly exhibit several pathogenic phenotypes, including hyperesthesia, neuronal damage, reduced motility, and early mortality. We further demonstrate TRPA-1/TRPA1 as a sensor for alpha-DCs, conserved between worms and mammals. Moreover, TRPA-1 activates SKN-1/Nrf via calcium-modulated kinase signaling, ultimately regulating the glutathione-dependent (GLO1) and co-factor-independent (DJ1) glyoxalases to detoxify alpha-DCs. Interestingly, this pathway is in stark contrast to the TRPA-1 activation and the ensuing calcium flux implicated in cold sensation in C. elegans, whereby DAF-16/FOX0 gets activated via complementary kinase signaling. Finally, a phenotypic drug screen using C. elegans identified podocarpic acid as a novel activator of TRPA1 that rescues alpha-DC-induced pathologies in C. elegans and mammalian cells. Our work thus identifies TRPA1 as a bona fide drug target for the amelioration of alpha-DC stress, which represents a viable option to address aging related pathologies in diabetes and neurodegenerative diseases.
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