Understanding the link between mutations in the enzyme PDE10A and hyperkinetic movement disorders

Arroyo Gutierrez, Hugo (2025) Understanding the link between mutations in the enzyme PDE10A and hyperkinetic movement disorders. MSc(R) thesis, University of Glasgow.

Abstract

The regulation of cyclic nucleotide levels, particularly by Phosphodiesterase 10A (PDE10A), is critical for neurological function, and its dysregulation is implicated in hyperkinetic chorea-like disorders such as Huntington’s Disease (HD). While PDE10A inhibition has been explored as a therapeutic strategy, clinical trials have yielded limited success, suggesting a more complex pathology than previously understood. Recent studies on PDE10A mutants propose that a loss of PDE10A function, rather than compensatory downregulation, may contribute to these symptoms.

This investigation uses biochemical techniques to characterize five newly identified human PDE10A mutants (A530T, Asn838AlafsTer46, E890D, R182Ter, and D1023_N1024insY), four of which are pathogenic and one (E890D) is non-pathogenic. Using immunoblotting, RT-qPCR, and confocal microscopy in HEK293T cells, I assessed protein expression, mRNA levels, subcellular localization, and PDE enzyme activity. Our findings reveal that the pathogenicity of early termination mutants, R182Ter and Asn838AlafsTer46, is not fully clear, and caused either by a lack of key functional domains or due to NMD degrading the mRNA of these mutants. In contrast, other pathogenic mutants (A530T and D1023_N1024insY) exhibited normal expression and localization, but showed a profound loss of phosphodiesterase activity.

• Item Type: Thesis (MSc(R))
• Qualification Level: Masters
• Subjects: Q Science > QR Microbiology; R Medicine > R Medicine (General)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Supervisor's Name: Baillie, Professor Geoge
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-85433
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 03 Sep 2025 15:50
• Last Modified: 03 Sep 2025 15:52
• Thesis DOI: 10.5525/gla.thesis.85433
• URI: https://theses.gla.ac.uk/id/eprint/85433