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Comments on Bose, Neelanjan et al. (2017) International Worm Meeting "A Caenorhabditis elegans Model to Study Age-related Complications Associated with Diabetes and Parkinson's Disease." (0)
Overview
Bose, Neelanjan, Chaudhuri, Jyotiska, Guha, Sanjib K., Gong, Jianke, Khateeb, Sana, Hall, David, Rifkind, Alexander, Liu, Jianfeng, Xu, X. Z. Shawn, & Kapahi, Pankaj (2017). A Caenorhabditis elegans Model to Study Age-related Complications Associated with Diabetes and Parkinson's Disease presented in International Worm Meeting. Unpublished information; cite only with author permission.
Aging and chronic hyperglycemia leads to the accumulation of reactive a-dicarbonyls (a-DCs), like methylglyoxal. a-DCs react rapidly with biological macromolecules, such as proteins, lipid, and DNA to generate Advanced Glycation End-products (AGEs). AGEs can enhance protein aggregation, cause cellular stress and inflammation that have been associated with aging and a number of age-related pathologies, including various forms of diabetic complications and neurodegenerative diseases. Evolutionarily conserved glyoxalases are responsible for a-DC detoxification to limit AGE stress; however their core biochemical regulation have remained unclear. We have established a Caenorhabditis elegans model, based on an impaired glyoxalase (glod-4/GLO1), to broadly study a-DC-related stress. We show that glod-4 animals rapidly exhibit several diabetes-like phenotypes including hyperesthesia, neuronal damage, and early mortality. We further demonstrate that the ion channel TRPA-1 acts as a novel sensor for a-DCs and AGEs, conserved between worms and mammals. Moreover, TRPA-1 activates SKN-1/Nrf2 via calcium-modulated kinase signaling, ultimately regulating the glutathione-dependent (glod-4/GLO1) and -independent (djr-1.1/DJ1 and djr-1.2/DJ1) glyoxalases to detoxify a-DCs and AGEs. We show that TRPA1-Nrf2 pathway is not only relevant for diabetic complications, but also provide protection against dopaminergic neuronal damage in C. elegans, as observed in Parkinson's disease (PD). We also show that synthetic AGE supplementation is sufficient to recapitulate significating diabetic and PD patholgies both in worms and mamalian systems. Finally, a phenotypic drug-screen using C. elegans identified podocarpic acid as an novel activator of TRPA-1 that rescues both diabetes and PD-related pathologies in C. elegans and mammalian cells. We propose that the upstream amelioration of a-DC stress represents a viable option to address related pathologies in diabetes and associated neurodegenerative conditions such as PD.
Authors: Bose, Neelanjan, Chaudhuri, Jyotiska, Guha, Sanjib K., Gong, Jianke, Khateeb, Sana, Hall, David, Rifkind, Alexander, Liu, Jianfeng, Xu, X. Z. Shawn, Kapahi, Pankaj
Affiliations:
- University of Michigan, Ann Arbor, MI
- Huazhong University of Science and Technology, Wuhan, Hubei, China
- University of California, San Francisco, San Francisco. CA
- Buck Institute for Research on Aging, Novato, CA