Mutations in Leucine Rich Repeat Kinase 2 [LRRK2] are a common cause of Parkinson’s disease. We have previously shown that LRRK2 regulates canonical Wnt signalling in different tissues and affects bone architecture. Wnt signalling has also long been known to be important for bone homeostasis.
We will investigate the interplay of LRRK2 and Wnt signalling affecting tibial bone architecture in health and disease. The project will combe micro-computed tomography, primary cell culture and immunohistochemistry with imaging of bone and signalling pathways in live genetically modified animals providing key insights into LRRK2 mediated Wnt signalling on bone in health and disease.
1.Berwick DC, Javaheri B, Wetzel A, Hopkinson M, Nixon-Abell J, Grannò S, Pitsillides AA, Harvey K  Pathogenic LRRK2 variants are gain-of-function mutations that enhance LRRK2-mediated repression of β-catenin signaling. Mol Neurodegener. 12: 9.
2.Nixon-Abell J, Berwick DC, Grannó S, Spain VA, Blackstone C, Harvey K  Protective LRRK2 R1398H Variant Enhances GTPase and Wnt Signaling Activity. Front Mol Neurosci. 9:18.
3.Madi K, Staines KA, Bay BK, Javaheri B, Geng, H, Bodey A, Cartmell S, Pitsillides AA, Lee PD.  Nanoscale strains in whole joints resolved via 4D synchrotron imaging. Nature Biomedical Engineering. doi: 10.1038/s41551-019-0477-1.
4.De Souza R, Javaheri B, Collinson RS, Chenu C, Shefelbine SJ, Lee PD, Pitsillides AA. . Prolonging disuse in aged mice amplifies cortical but not trabecular bones’ response to mechanical loading. J Musculoskeletal Neuronal Interact. 17:218-225
5.Javaheri B, Razi H, Gohin S, Wylie S, Chang Y-M, Salmon P, Lee PD, Pitsillides AA.  Lasting organ level bone mechanoadaptation is unrelated to local strain. Science Advances. 6: eaax8301. doi: 10.1126/sciadv.aax8301