Abstract

As well as being a kinase associated with age-dependent penetrant forms of Parkinsons disease, Leucine-rich repeat kinase 2 (LRRK2) is also an authentic GTP binding protein. There are mutations in the GTP-binding ROC (Ras of complex proteins) domain and the adjacent COR (C-terminal of ROC) in LRRK2 that cause Parkinsons disease.
The aim of this project is to understand why LRRK2 and related homologue LRRK1 bind GTP and what effect this has on the protein. Our ongoing work aims to identify proteins that bind to the ROC:COR domains of LRRK2, ie the GTP-binding region. We predict that understanding what these proteins are will give insight into the function of LRRK2 and may help understand mutations within those domains. We are currently pursuing interactions of LRRK2 with chaperones and co-chaperones, as well as novel interactors, in this region. At this point, we have mapped a series of interactions around the COR domain of LRRK2 that suggest that there is a multivalent protein complex. Ongoing work in the laboratory is aimed at understanding the functional impact of these interactions in cellular models.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000937-03
Application #
8552516
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2012
Total Cost
$399,757
Indirect Cost

  Institution

Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Blauwendraat, Cornelis; Reed, Xylena; Kia, Demis A et al. (2018) Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease. JAMA Neurol :
Liu, Zhiyong; Bryant, Nicole; Kumaran, Ravindran et al. (2018) LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network. Hum Mol Genet 27:385-395
Pellegrini, Laura; Hauser, David N; Li, Yan et al. (2018) Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice. Hum Mol Genet 27:3257-3271
Tomkins, James E; Dihanich, Sybille; Beilina, Alexandra et al. (2018) Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins. Proteomics 18:e1700444
Cookson, Mark R (2017) Mechanisms of Mutant LRRK2 Neurodegeneration. Adv Neurobiol 14:227-239
Langston, Rebekah G; Rudenko, Iakov N; Cookson, Mark R (2016) The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research. Biochem J 473:221-32
Roosen, Dorien A; Cookson, Mark R (2016) LRRK2 at the interface of autophagosomes, endosomes and lysosomes. Mol Neurodegener 11:73
Cookson, Mark R (2016) Cellular functions of LRRK2 implicate vesicular trafficking pathways in Parkinson's disease. Biochem Soc Trans 44:1603-1610
Cookson, Mark R (2015) LRRK2 Pathways Leading to Neurodegeneration. Curr Neurol Neurosci Rep 15:42
Civiero, Laura; Cirnaru, Maria Daniela; Beilina, Alexandra et al. (2015) Leucine-rich repeat kinase 2 interacts with p21-activated kinase 6 to control neurite complexity in mammalian brain. J Neurochem 135:1242-56

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