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Dissertation
Microtubule-severing proteins and their role in the development and degeneration of the central nervous system
Doctor of Philosophy (Ph.D.), Drexel University
Sep 2016
DOI:
https://doi.org/10.17918/etd-7174
Abstract
Neuronal cells are among the most morphologically elaborate cells in the human body. The creation, maintenance and modification of such high complexity are dependent on the organization of neuronal cytoskeleton elements. Microtubules play an essential role in this regard, thanks to their ability to form a resistant and yet plastic cytoskeleton. The acquisition of a more rigid or a more dynamic configuration depends upon the coordination of a large number of regulatory proteins. The present work is on a poorly characterized but translationally promising family of such regulatory proteins called microtubule-severing proteins. The work focuses on two such proteins in two different scenarios: fidgetin in neurodevelopment and spastin in neurodegeneration. Fidgetin was found to play a unique role in neurodevelopment by targeting the dynamic domain of the axonal microtubule as opposed to its stable domain, with fidgetin thus behaving as a microtubule plasticity suppressor. Its inhibition was found to boost the dynamic microtubule mass of the axon, thereby enhancing neuroplastic characteristics such as axon growth and the number of processes extended by an individual neuron. This profound effect on dynamic microtubules has interesting translational implications in neuropathology: from treating the injured central nervous system to better understanding neurodevelopmental disorders such as autism. On the other side of the spectrum, there is spastin, mutations of which cause a selective slow degeneration of first order neurons from the cortico-spinal tracts. The prevailing idea of this neurodegeneration is that neurotoxic effect of mutated spastin occurs through a loss-of-function mechanism. The present study challenges this concept by demonstrating the existence of an alternative gain-of-function mechanism of action. The data suggest that mutated spastin could induce neurodegeneration by aberrantly activating kinases, in particular casein kinase II, which in turn, compromises vital neuronal processes such as intracellular transport. Continuation of the work will open the door to a completely new translational paradigm to find an efficient treatment to this incurable condition.
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Details
- Title
- Microtubule-severing proteins and their role in the development and degeneration of the central nervous system
- Creators
- Lanfranco Leo - DU
- Contributors
- Peter W. Baas (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 7174; 991014632260704721