Project 3: LRRK2 Biology in Parkinson's Disease Parkinson's disease (PD) is a complex neurodegenerative disorder that is both sporadic and familial. It is currently thought that PD results from a combination of environmental factors and genetic susceptibility. Gene mutations in the leucine-rich repeat kinase 2 (LRRK2) have recently been shown to result in autosomal dominant PD. A high prevalence of these mutations in unrelated PD patients strongly suggests that mutant LRRK2 may play a key role in sporadic PD as well. The clinical and pathological phenotypes of LRRK2 PD patients are similar to classic late-onset PD, further emphasizing the potential importance of this gene. Biochemical evidence suggests that aberrant GTPase and kinase activities are linked to disease causing mutations, and may be at the basis of neuronal toxicity and pathogenesis of PD. The cell biology and pathobiological actions of LRRK2 are not yet known. To understand the role of LRRK2 in the function and dysfunction of neurons we have generated LRRK2 knockout mice and LRRK2 transgenic mice. With Cores B, C and D, we will study the neurochemical, neuroanatomical and behavioral changes in these mice as they age. We will explore the effects of oxidative stress in genetically engineered LRRK2 mice to examine the interplay of genetics and environmental effects on neuropathology. Since increased activity of LRRK2 is associated with neurotoxicity we will explore the cellular regulation of LRRK2 expression by the E3 ubiquitin ligase CHIP and its effects on neuronal viability. We expect that LRRK2 functions in large protein complexes and thus we propose to identify and characterize LRRK2 interacting proteins. The goals of this project are to identify and characterize the interaction of LRRK2 and its protein targets with the hope that these studies of LRRK2 may potentially lead to the development of novel therapeutic strategies for the treatment of PD.

Public Health Relevance

Gene mutations in LRRK2 are a common cause of familial and perhaps sporadic PD, yet little is know about how this protein functions, what cellular signaling networks it plays a role in and how mutations cause PD. The goals of this project are to understand the biology of LRRK2 to learn about the pathogenesis familial and sporadic PD and to identify potential new targets for future drug development to treat PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS038377-15
Application #
8533018
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
15
Fiscal Year
2013
Total Cost
$341,619
Indirect Cost
$133,315
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Martin, Ian; Kim, Jungwoo Wren; Dawson, Valina L et al. (2014) LRRK2 pathobiology in Parkinson's disease. J Neurochem 131:554-65
Dawson, Ted M; Dawson, Valina L (2014) Parkin plays a role in sporadic Parkinson's disease. Neurodegener Dis 13:69-71
Lee, Yun-Il; Giovinazzo, Daniel; Kang, Ho Chul et al. (2014) Protein microarray characterization of the S-nitrosoproteome. Mol Cell Proteomics 13:63-72
Siuda, Joanna; Jasinska-Myga, Barbara; Boczarska-Jedynak, Magdalena et al. (2014) Early-onset Parkinson's disease due to PINK1 p.Q456X mutation--clinical and functional study. Parkinsonism Relat Disord 20:1274-8
Fatokun, Amos A; Dawson, Valina L; Dawson, Ted M (2014) Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol 171:2000-16
Stafa, Klodjan; Tsika, Elpida; Moser, Roger et al. (2014) Functional interaction of Parkinson's disease-associated LRRK2 with members of the dynamin GTPase superfamily. Hum Mol Genet 23:2055-77
Martin, Ian; Kim, Jungwoo Wren; Lee, Byoung Dae et al. (2014) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 157:472-85
Tsika, Elpida; Glauser, Liliane; Moser, Roger et al. (2014) Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration. Hum Mol Genet 23:4621-38
Pirooznia, Sheila K; Dawson, Valina L; Dawson, Ted M (2014) Motor neuron death in ALS: programmed by astrocytes? Neuron 81:961-3
Lasagna-Reeves, Cristian A; Sengupta, Urmi; Castillo-Carranza, Diana et al. (2014) The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes. Acta Neuropathol Commun 2:56

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