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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2023)

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder, currently affecting over 7 million individuals worldwide. Clinically, PD results in progressive cell death of dopaminergic neurons in the basal ganglia and substantia nigra, but what drives this cell death is still unclear. Point mutations to the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are the most common cause of inherited PD and importantly, LRRK2-PD phenocopies sporadic PD. Thus, better understanding the roles of the LRRK2 protein could provide insights into the driving forces behind PD pathogenesis and progression. LRRK2 has several protein interaction domains and has been shown to be regulated by a number of interactors, yet adequate characterization of the LRRK2 protein interactome is still lacking. Chapter 1 will provide a comprehensive background on LRRK2 biology detailing its structure, function and interactions to inform topics explored in subsequent chapters. Chapter 2 identifies the E3 ubiquitin ligase TRIM1 as a novel regulator of LRRK2 microtubule localization and LRRK2 degradation by the proteasome. Chapter 3 comprises the first report of endogenous regulation of LRRK2 by a Rab protein. Endogenous Rab38 regulates LRRK2 subcellular localization in B16-F10 mouse melanocytes. Finally, Chapter 4 explores the effects of chloroquine and IFN-γ treatment on LRRK2 localization and activity in macrophages. This chapter reveals a novel interaction between LRRK2 and Rab32 in RAW 264.7 macrophages under IFN-γ treatment. These results highlight the need for further research into LRRK2 protein interactors which could regulate LRRK2 activity through a number of mechanisms in a cell-type specific manner.

    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2022)
    Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (tripartite motif family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2911-919, a nine amino acid segment within a flexible interdomain region (LRRK2853-981), which we designate the "regulatory loop" (RL). Phosphorylation of LRRK2 Ser910/Ser935 within LRRK2 RL influences LRRK2's association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 modulates LRRK2's interaction with Rab29 and prevents upregulation of LRRK2 kinase activity by Rab29 in an E3-ligase-dependent manner. Finally, TRIM1 rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, controlling its degradation, localization, binding partners, kinase activity, and cytotoxicity.
      Cover page: The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity
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