Cis- and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine induced neurodegeneration

Megha Jhanji, Chintada Nageswara Rao, Jacob C. Massey, Marion C. Hope, Xueyan Zhou, C. Dirk Keene, Tao Ma, Michael D. Wyatt, Jason A. Stewart and Mathew Sajish ()
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Megha Jhanji: University of South Carolina
Chintada Nageswara Rao: University of South Carolina
Jacob C. Massey: University of South Carolina
Marion C. Hope: University of South Carolina
Xueyan Zhou: Wake Forest School of Medicine
C. Dirk Keene: University of Washington School of Medicine
Tao Ma: Wake Forest School of Medicine
Michael D. Wyatt: University of South Carolina
Jason A. Stewart: University of South Carolina
Mathew Sajish: University of South Carolina

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Serum tyrosine levels increase during aging, neurocognitive, metabolic, and cardiovascular disorders. However, calorie restriction (CR) and sleep lower serum tyrosine levels. We previously showed that tyrosine inhibits tyrosyl-tRNA synthetase (TyrRS)-mediated activation of poly-ADP-ribose polymerase 1 (PARP1). Here, we show that histone serine-ADP-ribosylation is decreased in Alzheimer’s Disease (AD) brains, and increased tyrosine levels deplete TyrRS and cause neuronal DNA damage. However, dopamine and brain-derived neurotrophic factor (BDNF) increase TyrRS and histone serine-ADP-ribosylation. Furthermore, cis-resveratrol (cis-RSV) that binds to TyrRS mimicking a ‘tyrosine-free’ conformation increases TyrRS, facilitates histone serine-ADP-ribosylation-dependent DNA repair, and provides neuroprotection in a TyrRS-dependent manner. Conversely, trans-RSV that binds to TyrRS mimicking a ‘tyrosine-like’ conformation decreases TyrRS, inhibits serine-ADP-ribosylation-dependent DNA repair, and induces neurodegeneration in rat cortical neurons. Our findings suggest that age-associated increase in serum tyrosine levels may effect neurocognitive and metabolic disorders and offer a plausible explanation for divergent results obtained in clinical trials using resveratrol.

Date: 2022
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DOI: 10.1038/s41467-022-30785-8

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