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Mechanisms of Cellular Regulation and Post-translational Modification of LRRK2

This grant builds upon the research from a prior grant: Regulation of LRRK2 Membrane Association

Promising Outcomes of Original Grant:
We have identified methods to increase or decrease the ratio of cytosolic LRRK2 compared to membrane-localized LRRK2 as well as methods to increase or decrease the ratio of LRRK2 dimer compared to LRRK2 monomer. These findings are functionally significant and likely relevant to Parkinson’s disease because we found that the same treatments that decrease LRRK2 membrane localization and LRRK2 dimerization also decrease LRRK2-mediated cell toxicity and mitigate the effects of LRRK2 mutations causally linked to Parkinson’s disease.

Objectives for Supplemental Investigation:           
Our supplemental studies are aimed at further defining the sites within the LRRK2 protein that are most required for LRRK2 membrane localization and further defining the cellular mechanisms that regulate LRRK2 localization and oligomerization. These studies are important for guiding the development of novel therapies based on minimizing LRRK2-mediated toxicity and for understanding the biophysical properties of LRRK2, which associates with membranes despite the absence of any transmembrane sequences or known membrane association motifs.

Importance of This Research for the Development of a New PD Therapy:       
Mutations in LRRK2 are the most common cause of familial Parkinson’s disease. Although the mechanisms by which LRRK2 mutations cause PD are uncertain, in vitro studies indicate that LRRK2 mutations increase the kinase activity of LRRK2 and that the kinase activity is required for LRRK2-mediated cell toxicity. Because LRRK2 kinase activity is dependent upon LRRK2 membrane localization, our studies to define the sites within LRRK2 that are most required for LRRK2 membrane localization and the cellular mechanism that regulate LRRK2 membrane localization may identify novel therapeutic targets to mitigate the effects of LRRK2 mutations causally linked to Parkinson’s disease. 

Final Outcome

We have verified that LRRK2 undergoes key post-translational modifications that affect LRRK2 dimerization and LRRK2 membrane localization. We have generated a large set of LRRK2 variants that are now available to the Parkinson’s disease research community for testing the importance of specific LRRK2 amino acids for LRRK2 subcellular localization and function. Using these variants, we have determined that at least two distinct structural domains of LRRK2 undergo post-translational modifications that regulate LRRK2 membrane localization. We found that these post-translational modifications of LRRK2 also increased the specific association of LRRK2 with cholesterol-rich membrane domains, commonly termed “lipid rafts”, and extended the lifetime of the protein by protecting it from proteolytic degradation. In the course of these studies we observed that expression of a Parkinson’s disease-linked mutant LRRK2 stimulated the activity of the cell surface receptor for epidermal growth factor. This receptor, like many others, is partially distributed to lipid rafts. Therefore, we are pursuing the intriguing possibility that LRRK2 functions as a scaffold on the plasma membrane, or on internal membranes, to regulate the activation and transport of receptors.


  • Joseph P. Albanesi, PhD

    Dallas, TX United States

  • Matthew S. Goldberg, PhD

    Birmingham, AL United States

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