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Characterization of the Parkinson's Disease Associated Protein, Leucine-Rich Repeat Kinase 2 (LRRK2), as a Ras-Related GTPase

Gandhi, Payal

Abstract Details

2008, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder of the central nervous system that impairs control of voluntary movement. While the majority of cases are idiopathic, ~5-15% of cases have a genetic component. Studying these rare genetic forms of PD has highlighted key cellular pathways, which are believed to also be involved in the pathogenesis of the more common sporadic forms of disease. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of autosomal dominant PD and are also responsible for a significant number of idiopathic cases. LRRK2 is a multi-domain protein containing leucine-rich repeats, a Ras GTPase-like domain termed Roc, a mitogen-activated protein kinase kinase kinase (MAPKKK) domain and C-terminal WD40 repeats. This work characterizes LRRK2 as a Ras-related GTPase. LRRK2 is shown to be an authentic and functional GTPase, defined by the ability to bind GTP and undergo intrinsic GTP hydrolysis. The isolated Roc domain is sufficient for GTPase activity, suggesting that this catalytic process does not require additional domains of LRRK2. Additionally, LRRK2 mediated phosphorylation is stimulated upon GTP binding, suggesting that LRRK2 is a MAPKKK activated intramolecularly by its own GTPase. Since GTPases and MAPKKKs are upstream regulators of multiple signaling cascades, LRRK2 may play a central role in integrating pathways involved in neuronal cell signaling. The protein-protein interactions and pathways involved in LRRK2-mediated signaling remain elusive. In this work, microtubules are identified as a novel LRRK2-interacting protein. The Roc domain is sufficient for interaction with microtubules, however, this interaction occurs in a guanine nucleotide independent manner, suggesting that tubulin may not be an effector of LRRK2 GTPase activity. These findings link LRRK2 with microtubules, a structural component of the cell that is critically involved in the pathogenesis of several neurodegenerative diseases, including PD. Collectively, these studies provide focus for future efforts examining the regulation of LRRK2 GTPase activity and the functional significance of the LRRK2-microtubule interaction. Further elucidation of these aspects of LRRK2 biology will likely provide essential information that will aid in the development of novel therapeutics targeted against LRRK2-mediated PD.
Amy Wilson-Delfosse (Advisor)
209 p.

Recommended Citations

Citations

  • Gandhi, P. (2008). Characterization of the Parkinson's Disease Associated Protein, Leucine-Rich Repeat Kinase 2 (LRRK2), as a Ras-Related GTPase [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1195574448

    APA Style (7th edition)

  • Gandhi, Payal. Characterization of the Parkinson's Disease Associated Protein, Leucine-Rich Repeat Kinase 2 (LRRK2), as a Ras-Related GTPase. 2008. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1195574448.

    MLA Style (8th edition)

  • Gandhi, Payal. "Characterization of the Parkinson's Disease Associated Protein, Leucine-Rich Repeat Kinase 2 (LRRK2), as a Ras-Related GTPase." Doctoral dissertation, Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1195574448

    Chicago Manual of Style (17th edition)