title: A Caenorhabditis elegans Model Elucidates a Conserved Role for TRPA1-Nrf Signaling in Reactive α-Dicarbonyl Detoxification.
abstract: Reactive α-dicarbonyls (α-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 α-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 α-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 α-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 α-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/FOXO 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 α-DC-induced pathologies in C. elegans and mammalian cells. Our work thus identifies TRPA1 as a bona fide drug target for the amelioration of α-DC stress, which represents a viable option to address aging-related pathologies in diabetes and neurodegenerative diseases.
authors: The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: Jyotiska
authors: J
authors: Chaudhuri
authors: The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA; Department of Urology, University of California, 400 Parnassus Avenue, San Francisco, CA 94143, USA.
authors: Neelanjan
authors: N
authors: Bose
authors: College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China; Life Sciences Institute and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Jianke
authors: J
authors: Gong
authors: The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: David
authors: D
authors: Hall
authors: The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: Alexander
authors: A
authors: Rifkind
authors: The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: Dipa
authors: D
authors: Bhaumik
authors: The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: T Harshani
authors: TH
authors: Peiris
authors: The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: Manish
authors: M
authors: Chamoli
authors: The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: Catherine H
authors: CH
authors: Le
authors: College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
authors: Jianfeng
authors: J
authors: Liu
authors: The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: Gordon J
authors: GJ
authors: Lithgow
authors: The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors: Arvind
authors: A
authors: Ramanathan
authors: Life Sciences Institute and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: X Z Shawn
authors: XZS
authors: Xu
authors: The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA; Department of Urology, University of California, 400 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: pkapahi@buckinstitute.org.
authors: Pankaj
authors: P
authors: Kapahi
mesh_terms: D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins; D011765:Pyruvaldehyde
keywords: Caenorhabditis elegans; Nrf2; Skn-1; TRPA1; advanced glycation endproducts; aging; diabetic complications; glyoxalase; neuropathy; α-dicarbonyl stress