Dissertation
Restoring protein synthesis in a neuronal model of Charcot-Marie-Tooth disease
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2025
DOI: 10.25820/etd.008209
Abstract
Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy characterized by progressive sensory dysfunction and muscle weakness that begins in the distal limbs and spreads proximally. More than one hundred genes are implicated in CMT, with enrichment for activities in myelination, axon transport, and protein synthesis. A large proportion of these implicated genes encode cytoplasmic aminoacyl-tRNA synthetases (aaRS), enzymes essential for charging tRNAs. The recurring involvement of aaRS suggests a shared pathogenic mechanism linking protein synthesis to CMT pathology. To address this question, I investigated how CMT-associated aaRS variants affect protein synthesis and neuronal vulnerability. Expression of CMT-linked variants in tyrosyl-tRNA synthetase (CMT-YARS) in primary sensory neurons produced a marked reduction in production synthesis, preceding the onset of caspase dependent axon degeneration and cell death. Surprisingly, dissociating and replating these neurons, a procedure that stimulates axon regeneration, restored protein synthesis in an mTOR-dependent manner. CMT-YARS neurons also displayed a reduction in short-lived axon maintenance factors, NMNAT2 and STMN2. Depletion of these factors sensitized the neurons to SARM-1 dependent cell death after exposure to a secondary stressor, when otherwise this stressor is non-toxic. Collectively, this work highlights the diverse framework of CMT and the different avenues through which new treatment strategies may be developed. For instance, rescuing protein synthesis in CMT mutant neurons could offer new and exciting therapeutic options beyond symptom management.
Details
- Title: Subtitle
- Restoring protein synthesis in a neuronal model of Charcot-Marie-Tooth disease
- Creators
- Julianna Koenig
- Contributors
- Daniel Summers (Advisor)Sheila Baker (Committee Member)Jan S Fassler (Committee Member)Michael Dailey (Committee Member)C Andy Frank (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biology
- Date degree season
- Autumn 2025
- DOI
- 10.25820/etd.008209
- Publisher
- University of Iowa
- Number of pages
- viii, 101 pages
- Copyright
- Copyright 2025 Julianna Koenig
- Language
- English
- Date submitted
- 12/09/2025
- Description illustrations
- illustrations, graphs
- Description bibliographic
- Includes bibliographical references (pages 88-101).
- Public Abstract (ETD)
- Neurons are the building blocks of the nervous system, enabling individuals to perceive and interact with the world around them. In order for neurons to survive and function properly in the nervous system, they have developed a number of unique cellular processes. When any one of these processes goes wrong, either through disease or injury, the neuron becomes prone to dysfunction and death. One of the most common genetically inherited diseases that damages neurons this way is Charcot-Marie-Tooth disease (CMT). Though how CMT damages neurons is still unclear, research over several decades has highlighted a family of proteins that are often mutated in CMT. These proteins are aminoacyl-tRNA synthetases (aaRS) which are required for the neuron to assemble proteins. As such, we can expect that issues with aaRS will negatively impact protein creation and drive the neuron to degeneration. My work focuses on testing mutant versions of aaRS to determine if, indeed, they impair protein creation. We discovered that expressing mutant aaRS in cultured sensory neurons causes a decrease in the rate of protein creation. Furthermore, triggering regeneration in the cultured neurons by lifting them off their plate and culturing them onto a new one repairs the neuron s ability to make proteins. Discovering ways to trigger this regeneration program is crucial for the development of new CMT therapies, as we would be able to target one of the things that goes wrong in CMT patient neurons.
- Academic Unit
- Biology
- Record Identifier
- 9985135148502771
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