Author

Megha Jhanji

Date of Award

Fall 2021

Document Type

Open Access Dissertation

Department

College of Pharmacy

First Advisor

Sajish Mathew

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, and it currently affects more than 50 million people worldwide. Much of the population develop late-onset AD after 65 and constitute more than 95% of the cases. Currently, there is no definitive cure or way to slow down the progression of this disease that addresses the neurodegeneration and loss of cognitive functions. Although the underlying cause of AD is still unknown, the “amyloid cascade hypothesis” attributed it to the aggregation of amyloid beta (AU+03B2) peptides and has been the focus for targeting most disease-modifying drugs in clinical trials. However, emerging works suggest that the causal effects of AD may not be limited to Aβ alone and that inhibition of its production can lead to exacerbation of cognitive impairment in AD patients. The molecular pathways affected in AD include loss of synapse, accumulation of oxidative DNA damage, and impairment of protein synthesis, which are majorly affecting the ability of the brain to form and store memory.

In this dissertation, our analysis using publicly available metabolomics data showed that serum tyrosine level increases during aging and is also an underappreciated biomarker for various neurocognitive, cardiovascular, and metabolic diseases. Concomitantly, our bioinformatics analysis using publicly available transcriptomics and brain proteomic data showed that tyrosyl-tRNA synthetase (TyrRS) that activates tyrosine for protein synthesis and helps in DNA repair shows the highest expression in the cerebral cortex and is significantly reduced in the affected brain regions of AD patients. Despite the correlation of brain protein levels of TyrRS with human cognitive performance and AD disease progression, intriguingly, the brain TyrRS levels did not correlate with any known biomarkers of neurodegeneration, suggesting that brain TyrRS level is modulated through hitherto unknown factors and mechanisms.

During our exploration to unravel the molecular mechanism and signaling pathways that would potentially modulate neuronal TyrRS levels, we serendipitously discovered that tyrosine itself is a potential causal agent that depletes TyrRS levels in neurons. In contrast, dopamine - a tyrosine-derived neurotransmitter, stimulates the de novo synthesis of neuronal TyrRS. Furthermore, we previously showed that tyrosine inhibits nuclear TyrRS-mediated activation of the auto-poly-ADP-ribos(PAR)ylation of poly-ADP-ribose polymerase 1 (PARP1). Intriguingly, inhibition of the auto-PARylation of PARP1 ‘traps’ PARP1 on the damaged DNA and inhibits the repair of oxidative DNA damage. Consistently, here we found that tyrosine depletes nuclear TyrRS and is a potent inducer of neuronal oxidative DNA damage. Taken together, our findings in this dissertation suggest that an age-associated increase in serum tyrosine level may have causal effects not only in aging but also in various metabolic and neurocognitive disorders, including AD.

We previously showed that resveratrol is a natural molecule that binds to TyrRS. However, trans-resveratrol brought mixed outcomes in clinical trials, and the molecular basis remained an unresolved scientific problem. In this work, we discovered that trans-resveratrol (trans-RSV) that binds to TyrRS in a ‘tyrosine-like' conformation decreases TyrRS levels, causing oxidative DNA damage and neurotoxicity. In contrast, cis-RSV that binds to TyrRS in a ‘tyrosine-free’ conformation increased TyrRS levels, facilitated DNA repair, and provided neuroprotection in a TyrRS-dependent manner. Our novel findings thus offer a possible explanation for trans-RSV mediated detrimental effects such as increased brain volume loss in AD patients, worsening memory in schizophrenia, and increased cardiovascular risk, like the effect of high concentrations of trans-RSV that deplete TyrRS and cause neurotoxicity. On the other hand, studies reporting low dose RSV reporting cognitive benefits and protection from heart failure used doses equivalent to low concentrations of trans-RSV that act like cis-RSV, increasing TyrRS and was neuroprotective. In addition to explaining the apparent benefits associated with low doses of trans-RSV, our work suggests that cis-RSV or the use of cis-RSV as a pharmacophore may help develop drugs against age-associated neurological disorders and metabolic diseases.


Available for download on Wednesday, November 30, 2022

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