Mir-34 Regulates Brain Aging And Susceptibility To Neurotoxicity In Drosophila Melanogaster

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Doctor of Philosophy (PhD)
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Neuroscience and Neurobiology
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Srinivasan, Ananth

Aging is one of the most prominent risk factors for neurodegenerative disease. As a society, we are facing an exponential growth in our elderly population. With it, we see increased cases of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and ALS. At this time, there are still a variety of unknowns regarding how best to treat these diseases. The use of basic research to study the biology of aging has been an integral source of information when considering how to combat these age-associated diseases. Here, we used the Drosophila melanogaster model system to study brain aging and susceptibility to disease. We focused our attention on studying the microRNA miR-34. MiR-34 has been previously shown to be a potent regulator of brain health and lifespan in the fly model. In the absence of miR-34, animals have reduced lifespans and accelerated brain degeneration. In our studies, we transcriptionally profiled the brains of animals with null mutations for miR-34. From this, we identified a series of protein homeostasis impairments in the mutant brain. In trying to understand a mechanism for this molecular phenotype, we identified Lst8, a subunit of TOR Complex 1 and 2, as a target of miR-34. Lst8 upregulation was capable of recapitulating only a select aspect of the miR-34 mutant phenotype, suggesting that additional targets may contribute to the protein homeostasis impairment. We performed additional studies on the mutant brain to understand the degree to which it promotes age-associated phenotypes at a younger state. From this work, we identified a set of similarities between the younger mutant brain and the older control brain, creating a better understanding of how miR-34 regulates aging in the brain.

Nancy M. Bonini
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