- Degrade or degenerate
- Glial protein degradation in Huntington’s disease
C.J.F. van Noorden
- Award date
- 12 April 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Huntington’s disease (HD) is a dominant inherited neurodegenerative disorder caused by a CAG expansion in the Huntingtin gene, which leads to a polyglutamine expansion in the mutant Huntingtin protein (mHTT) and its aggregation in nuclear and cytoplasmic inclusions. mHTT degradation can in principle counteract the toxic effects of mHTT. Intracellular protein degradation occurs via two routes: the macroautophagy pathway and the ubiquitin-proteasome system (UPS). Although the polyglutamine-expanded HTT protein is ubiquitously expressed, neurons appear to be the most sensitive. In contrast, neighbouring glia seem less affected. Glia are essential for proper brain function as they play a role in synaptic communication and have been shown to be involved in several neurodegenerative diseases. In this thesis, we examine whether the apparent selective vulnerability of neurons is due to differences in protein degradation between neurons and glia . We show that there is no impairment of the UPS in HD, as proteasomes and ubiquitin are dynamically recruited into mHTT inclusions and that active enzymes of the UPS are present. We demonstrate that the nuclear inclusion frequency is higher in neurons compared to GFAP-positive astrocytes and microglia in different HD mouse models and that these results correlate with the mHTT half-life in corresponding cell lines. These observed differences between neurons and glia in mHTT half-life may indeed be due to our observed differences in the UPS and autophagy between glial and neuronal cell lines. Together, these findings contribute to a deeper understanding of the dissimilarities in mHTT inclusions between different cell types in the brain.
Thesis (complete) (Embargo up to and including 12 April 2019)
Chapter 3. Dynamic recruitment of ubiquitin to mutant huntingtin inclusion bodies (Embargo up to and including 12 April 2019)
Chapter 5. Delayed mHTT degradation in striatal neuronal cells compared to glia (Embargo up to and including 12 April 2019)
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library, or send a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.