Investigating The Role of Pancreatic eIF2-alpha kinase (PEK) In DLK/ Wallenda (Wnd)-mediated Neurodegeneration In Drosophila
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Authors
Quagraine, Yaw Acquaah
Issue Date
2025
Type
Thesis
Language
en_US
Keywords
DLK/ Wnd , Drosophila , Neurodegeneration , Neurons , PEK
Alternative Title
Abstract
Neurons, the cells that are electrically excitable and form the basis of the nervous system, display an impressive range of morphologies and functions, which together drive processes from sensation and movement to cognition. These unique and mighty cells also have developed unique features such as dendrites as the recipient of signals, axons as wire for transmitting signals, and sophisticated protein localization and axonal transport for protein function and cellular homeostasis. However, neuronal homeostasis is constantly challenged by various intrinsic and extrinsic stressors, and results mislocalization and aggregation of these proteins occurs, subsequently resulting in functional and structural alterations in neurons, and leading to neuronal dysfunction and death, the characteristic features of neurodegenerative diseases. The highly conserved Unfolded Protein Response (UPR) kinase Pancreatic eIF-2α kinase (PEK) and the Dual Leucine Zipper Kinase (DLK) signaling kinase Wallenda (Wnd) are important regulators of neuronal health and neurodegeneration. Although these two (2) kinases are very important, their interaction in degenerative and regenerative responses are not fully understood. Therefore, understanding their cellular and molecular link is essential for fast-tracking the treatment of neurodegenerative disorders. Chapter 1 describes the mechanisms of protein homeostasis, including subcellular localization and axonal transport, essential for their survival. It highlights how the disruption of these fundamental processes leads to protein mislocalization and aggregation, which are central to neurodegenerative diseases.
Chapter 2 we investigate the novel regulatory and functional interaction between the ER stress kinase PEK and the axonal integrity regulator DLK/Wallenda (Wnd) in Drosophila. We demonstrate that overexpression of either PEK or DLK/Wallenda induces severe neurodegeneration and axonal arborization, and, critically, that PEK modulates Wnd's axonal enrichment, a defect rescued by PERK inhibition in neurodegenerative disease models. Our findings highlight PEK and DLK signaling are intertwined in degenerative and regenerative neuronal responses, revealing therapeutic potential for targeting this pathway in neurodegenerative conditions.
Finally, Chapter 3 discusses and addresses future directions, focusing on elucidating the precise molecular mechanisms by which PEK regulates Wnd axonal enrichment and influences its activity.
This thesis provides insights to current understanding of the interplay of PEK and DLK/ Wnd in neurons using Drosophila models.