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Cdk12 maintains the size of the proximal axon and the actin barrier

Townsend, Louise 2022. Cdk12 maintains the size of the proximal axon and the actin barrier. PhD Thesis, Cardiff University.
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Abstract

Neurons involved in brain functions such as learning, memory, and emotion rely on neuronal polarity to receive information and transmit this unidirectionally to other neuronal cells or tissues. In order to maintain neuronal polarity, the neuron relies on two structurally and functionally different regions, the axonal and somatodendritic domains that are separated by molecular barriers in the proximal axon to selectivity sort, transport and deliver axonal and dendritic proteins. One barrier, the axon initial segment (AIS), that functions in action potential initiation has a distinct structure and uses an actin-based filter and microtubule binding to filter cargo. Recent work suggests that these molecules and structure are conserved in the model organism, Drosophila melanogaster. However, how this neuronal sub compartment is maintained and whether other molecules are involved in its function and integrity remains unknown. This thesis demonstrates that cyclin-dependent kinase 12 (Cdk12), previously identified in an unbiased genetic screen, controls proximal axon width and neuronal survival. Using actin as an AIS marker, it was shown that Cdk12 interferes with actin dynamics and form actin swellings in the proximal axon. These actin changes altered the selectivity filter in the AIS and facilitated peroxisomes (a vesicle marker of the soma) to enter the axon. Based on the previous findings, this thesis also aimed to investigate the physiological effect the loss of Cdk12 had on neuronal changes and on other organelles in the neuron. This thesis demonstrated that Cdk12 influences neuronal Ca2+ levels, ER distribution and mitochondria morphology in the proximal axon in the stages prior to neurodegeneration. Therefore, Cdk12 is crucial to maintain the size and function of the AIS and to regulate neuronal physiology. This in turn regulates neuronal polarity which, if disrupted, leads to neurodegeneration, a key characteristic seen in many neurodegenerative diseases.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > Q Science (General)
Date of First Compliant Deposit: 13 January 2023
Date of Acceptance: 13 January 2023
Last Modified: 10 Feb 2024 02:14
URI: https://orca.cardiff.ac.uk/id/eprint/155833

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