Almudimeegh, Sultan;
(2022)
Modulation of LRRK2 mediated signaling in immune cells.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Mutations in LRRK2 are considered the most common cause of familial and sporadic Parkinson’s disease (PD), a neurodegenerative movement disorder. PD is characterised pathologically by the death of dopaminergic neurons and symptomatically by tremor, bradykinesia and impaired coordination. LRRK2 variants is also linked to an increased risk of Crohn's inflammatory bowel disease and increased susceptibility to leprosy. All those diseases share a common immune dysfunction theme. The exact physiological function of LRRK2 remains largely elusive. However, multiple reports suggest that LRRK2 is involved in Wnt and NFAT signalling. Those pathways are known to mediate a variety of physiological functions, including immune system regulation and synaptic functions. In this study, I investigate the role of LRRK2 in mediating the inflammatory responses in macrophages and T cells and associated changes in Wnt signalling components. Challenging the LRRK2 WT and LRRK2 KO RAW 264 macrophages with Lipopolysaccharides (LPS) resulted in changes in the release of Nitric oxide (NO) and expression of several cytokines, including tumour necrosis factor-alpha (TNFα), cyclooxygenase-2 (COX-2) and others. Furthermore, the phagocytic activity of the LRRK2 KO cells appears to be substantially lower compared to LRRK2 WT cells. I observed changes in Wnt signalling activity in response to LPS across the different genotypes. Interestingly, the expression of the LRRK2 kinase substrate RAB10 and its phosphorylated form, decreased significantly in response to LPS in LRRK2 KO cells compared to WT, providing a possible mechanistic explanation for the decrease in cytokines and NO release. Wnt-related changes were confirmed ex-vivo in bone-marrow-derived macrophage (BMDM) and T cells across WT, KO and G2019S genotypes. In conclusion, this study substantiates a role for LRRK2, in mediating inflammatory responses in immune cells and highlights the significance of Wnt signalling and Rab10 in this LRRK2 immune function.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Modulation of LRRK2 mediated signaling in immune cells |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10143626 |
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