Statement of Work. The research proposed in this multi-PI application with three PIs (Drs. Hoang, Yue and Ubarretxena) combines the efforts of three different laboratories to study the structure and activity regulation of Leucine Rich Repeat Kinase 2 (LRRK2). Mutations in this unique multi- domain enzyme have been linked with Parkinson's disease (PD) pathogenesis, and thus LRRK2 has emerged as a key therapeutic target for the treatment of this neurodegenerative disorder. The results obtained from X-ray crystal structures of the GTPase domain and the COR region carrying PD-linked mutations (Dr. Hoang component) and those obtained from the high- resolution electron microscopy 3-D models of full-length LRRK2 (Dr. Ubarretxena component) will be used to inform the biochemical, cell-based and animal studies (Dr. Yue component). In particular, we will learn how the GTPase and kinase activities in LRRK2 are coordinated and how domain-domain interactions in the enzyme, and PD-linked mutations affect these activities.

Public Health Relevance

Leucine rich repeat kinase 2 (LRRK2) is a multi-domain enzyme with GTPase and kinase activities that is involved in the pathogenesis of Parkinson's disease (PD) and has become an important target for the development of therapeutic strategies against this neurodegenerative disorder. However, in spite of the critical role of LRRK2 in PD there is relatively little structural information available on this unique mutli-domain enzyme. As such, the action mechanism of LRRK2 remains largely elusive. There is no understanding of the overall architecture of LRRK2 or the nature of the interplay between its GTPase and kinase activities. We will use a combined structural, biochemical, and functional approach to uncover how domain structure and protein-protein interactions affect the interplay between GTPase and kinase structure in LRRK2 and its role in PD pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM115844-04
Application #
9706879
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Barski, Oleg
Project Start
2016-06-01
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Bassil, Fares; Fernagut, Pierre-Olivier; Bezard, Erwan et al. (2016) Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy. Proc Natl Acad Sci U S A 113:9593-8
Wang, Wei; Nguyen, Linh T T; Burlak, Christopher et al. (2016) Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein ?-synuclein. Proc Natl Acad Sci U S A 113:9587-92
Hoang, Quyen Q (2014) Pathway for Parkinson disease. Proc Natl Acad Sci U S A 111:2402-3