Doctoral defence „Distinct roles of miR-146a and miR-146b in neurons and microglia“

On June 9 Keerthana Chithanathan will defend her neuroscience doctoral thesis „Distinct roles of miR-146a and miR-146b in neurons and microglia“.

Supervisors:
Professor emerita Aleksandr Žarkovski, University of Tartu
Professor Li Tian, University of Helsinki (Finland)
Professor Ana Rebane, University of Tartu
Research fellow Monika Jürgenson, University of Tartu

Opponent:
Professor Tomi Rantamäki, University of Helsinki (Finland)

Summary:
The brain constantly adapts to different challenges, and this flexibility relies on precise molecular control. One important group of molecules involved in this process is microRNAs (miRNAs), which help regulate gene activity. Among them, the miR-146 family, consisting of miR-146a and miR-146b, plays a key role in controlling inflammation and immune responses in the brain. Studies have demonstrated that dysregulation of miR-146a/b might be implicated in the development on neurodegenerative and psychiatric disorders. This thesis explores the specific roles of miR-146a and miR-146b in neurons and microglial cells using genetically modified mice. We found that miR-146b is mostly present in neurons, the cells responsible for processing information. When miR-146b was removed, we observed more neurons and improved memory, suggesting that this molecule normally helps fine-tune brain's cognitive function. These effects were linked to increased levels of Gdnf, a growth factor associated with neuronal survival and function. On the other hand, miR-146a is mainly found in microglial cells, which are the brain’s immune cells. These cells protect the brain by responding to infections and injuries. When we triggered an inflammatory response, mice without miR-146b showed less sickness behavior, reduced microglial activation, and lower levels of inflammatory molecules. Interestingly, these changes were linked to an increase in miR-146a, revealing a balancing act between the two miRNAs in controlling brain inflammation. We also examined how miR-146a responds to long-term metabolic stress, such as a high-fat diet (HFD), which is known to accelerate brain aging. We found that miR-146a levels decreased in mice on an HFD, leading to signs of premature aging in brain immune cells. Importantly, treatment with elocalcitol, a vitamin D analog, restored miR-146a levels and reduced brain aging in normal mice, but not in those lacking miR-146a. This confirms that elocalcitol’s protective effects depend on miR-146a. These findings highlight the importance of miR-146a and miR-146b in maintaining brain health by regulating neurons and microglial cells. Understanding how these molecules work could lead to new treatments for brain disorders linked to inflammation and metabolism.

You can also watch the defense via Teams.