Open Collections

Witt, Skyla Ivory

University of British Columbia

Background: Huntington disease (HD) is an inherited progressive neurodegenerative disorder disease caused by a CAG repeat expansion mutation in the HTT gene. CAG repeat number correlates with age of onset with higher repeats causing earlier onset of symptoms. The impact of mutant HTT (mHTT) on neurons, astrocytes, and microglial cells has been studied in detail, in contrast to its impact on oligodendrocytes, the myelinating cells of the central nervous system. Imaging studies in HD patients and mouse models have shown that white matter pathology precedes symptoms and neuronal degeneration. Furthermore, animal model studies have shown that when mHTT is removed from oligodendrocyte progenitors, myelination improves suggesting mHTT has a direct detrimental effect on oligodendroglia. I hypothesize that mHTT alters oligodendrocyte development, maturation and myelination in a CAG repeat specific manner. Methods: I created a cerebral forebrain model patterned for oligodendrocyte growth and characterized this model. I then investigated the transcriptomic profile of oligocortical organoids expressing mHTT with adult onset (45 CAG repeats, or mHTT-45Q) or juvenile onset (81 CAG repeats, mHTT-81Q). I compared the transcriptional profiles to identify differences between them and then focused on changes in oligodendrocyte-specific genes of direct relevance to the oligodendroglia and myelination deficits being studied. Results: Although oligodendrocyte genes were expressed in the oligocortical organoids at 14 weeks post-differentiation, the levels of these genes were comparable to the general cerebral forebrain model. A greater number of differentially expressed genes were observed in mHTT-81Q organoids compared with mHTT-45Q. Oligodendrocyte specific transcriptional changes showed organoids with mHTT-81Q were mostly affected during earlier periods of development and maturation in oligodendrocytes whereas organoids containing mHTT-45Q had more of an affect on the later stages of maturation oligodendrocytes. This suggests individuals with a higher CAG tract size will have earlier detrimental effects on oligodendrocyte development than individuals who have adult onset. Conclusion: mHTT is seen to have an effect on oligodendrocyte development, maturation and myelination in a CAG repeat specific manner, suggesting that the white matter and myelination pathology in HD is likely to reflect both developmental and degenerative changes.

Text

2025-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88520

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/