Interplay of Brain Derived Neurotrophic Factor and Protein Kinase A in Modulating Mitochondrial Structure and Function in Brain Homeostasis and Disease
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Authors
Swain, Maryann
Issue Date
2023
Type
Dissertation
Language
Keywords
Alzheimer's Disease , BDNF , Mitochondria , Neurons , Parkinson's Disease , PKA
Alternative Title
Abstract
Abstract:Neurons are postmitotic cells that contain elongated specialized structures that emanate from their cell bodies termed neurites (axons and dendrites). In order to form neuronal networks, neurons rely on continuous neurotrophic support mediated by Brain-Derived Neurotrophic Factor (BDNF). My dissertation work characterized new physiological roles that BDNF play in maintaining neuronal homeostasis, specifically by regulating mitochondrial structure and function and neuronal metabolism. Specifically, I found that exposure of neurons to the mature form of BDNF which binds and activates the Tropomyosin Kinase β (Trkβ) receptor to promote rapid endocytosis and translocation of the signaling endosome to the mitochondria leading to elevated activation of Protein Kinase A (PKA). BDNF-mediated activation of mitochondrial PKA led to an increase in phosphorylation of fission modulator Drp1, and of mitochondrial adaptor protein Miro-2 to promote mitochondrial elongation and increase the trafficking and content of mitochondria in dendrite trees. Secondly, exposure of neurons to BDNF enhanced neuronal metabolism (oxidative phosphorylation and glycolysis) and increased the transmembrane potential of mitochondria; processes that required activation of trkβ. Furthermore, BDNF-mediated enhancement of mitochondrially-localized PKA was associated with increased resistance of primary cortical neurons against neurodegeneration and oxidative stress induced by rotenone or exposure to amyloid β, in vitro models of Parkinson’s and Alzheimer’s disease respectively. Finally, I provide new methodology that I co-developed that allows neuroscientists to analyze neuronal metabolism and connectivity in the same population of neurons in a rigorous manner by multiplexing the Seahorse XFe24 analyzer with ImageXpress® Nano high content imaging microscopes. By using this novel methodology, I was able to characterize the temporal effects of BDNF on brain energy production and connectivity with high resolution. Overall, my dissertation work provides new mechanisms by which BDNF exerts neuroprotection that goes beyond the classical model of inhibition of apoptosis signaling. Specifically, by BDNF activating mitochondrially localized PKA to govern mitochondrial structure/function which increases neuronal survival and connectivity.