The molecular mechanism of Dual leucine zipper kinase protein localization in neuronal stress signaling.
Loading...
Authors
Kim, Seung Mi
Issue Date
2024
Type
Dissertation
Language
en_US
Keywords
axon terminals , DLK , protein turnover , Rab11 , Wallenda
Alternative Title
Abstract
Neurons, fundamental operational units of the nervous system, are intricately polarized cells comprised of three primary components: dendrites, a cell body, and an axon. Due to their distinct functions, precise protein localization within neurons is essential for maintaining neuronal homeostasis. Certain proteins exhibit notable enrichment in axon terminals, where they exert pivotal influences on neuronal function, morphology, and survival. Dual Leucine Zipper Kinase (DLK) modulates neuronal stress responses, including neuronal loss implicated in various neurodegenerative conditions. DLK is axonally expressed and is under constant suppression under normal conditions. Although DLK is known to localize in axons and has crucial roles, the mechanisms governing DLK localization in axons remain elusive. Therefore, understanding the molecular mechanisms of DLK localization is paramount for elucidating its functions and advancing therapeutic strategies for numerous neurodegenerative diseases. Chapter 1 describes known mechanisms involved in protein localization in neurons, such as transport, local synthesis, diffusion, and degradation. Rab GTPases are crucial in regulating the interaction between cargoes and localization machinery. Moreover, this chapter demonstrates that disruptions in these mechanisms impair proper protein localization, leading to various neurodegenerative diseases.
In Chapter 2, we find that Wallenda (Wnd), the Drosophila ortholog of DLK, is highly enriched in the axon terminals, and such localization is essential for Highwire-mediated suppression of Wnd protein levels. Moreover, Rab11 plays a critical role in regulating Wnd protein turnover to inhibit excessive neuronal loss.
Finally, Chapter 3 discusses and addresses future directions, focusing on the study of palmitoylation-defective Wnd mutants, wild-type Wnd axon transport, and protein turnover machinery.
This thesis provides a novel demonstration of the functional role of axonal protein localization in protein turnover to maintain stable stress signaling. Furthermore, it defines the fundamental molecular mechanisms of the initial motif and axonal sorting pathway from the cell body to the axon terminals, leading to more predictive models of protein localization. As a result, demonstrating the role of axonal protein localization will offer new insights into its function in neurons.